Injection spring for aged prefilled syringe and auto injector

ABSTRACT

A method of adapting an auto injector configured to actuate a prefilled syringe, the auto injector having a biasing member having a spring constant, the prefilled syringe being filled with a volume of therapeutic fluid, the prefilled syringe including a barrel, stopper, and a needle, the stopper having a path of travel, the biasing member arranged to move the stopper along the path of travel. An auto injector having an injection spring adapted to an aged prefilled syringe.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is being filed on 19 Sep. 2019, as a PCT Internationalpatent application, and claims priority to U.S. Provisional ApplicationSer. No. 62/734,209 filed Sep. 20, 2018, the entire contents of whichare hereby expressly incorporated herein by reference.

BACKGROUND

An auto injector is a device for automatically injecting therapeuticfluid into a patient. Auto injectors have had rapidly increasingpopularity over recent years due to a variety of factors. For example,auto injectors are convenient for both caregivers and for patients whoself-administer therapeutic fluids. They decrease the number of stepsrequired to administer therapeutic fluid. Moreover, because autoinjectors are labeled and the syringes are prefilled by suppliers of themedications, there is no need to manually fill the syringe using vialsof therapeutic fluid. The use of prefilled syringes reduces the risk oferrors in dosage, misidentification of the medication, andcontamination.

In use, an auto injector is typically loaded with a prefilled syringeand has a compressed spring or other biasing member for pushing astopper to eject the therapeutic fluid. A button or other actuator isconnected to a mechanism for releasing the compressed spring so that itextends. As the spring extends, it drives a piston rod or plunger, whichin turn pushes the stopper within the syringe. The stopper then expelsthe therapeutic fluid from the syringe barrel, through the needle, andinto the patient's tissue at the site of administration.

Before bringing a pharmaceutical product such as a prefilled syringe andauto injector on the market, a company typically must gain approval froma government regulatory agency such as the United States Food and DrugAdministration or similar agency in foreign countries. For drugscontained in prefilled syringes and delivered through auto injectorsystems, a pharmaceutical company typically needs to provide the agencywith stability testing reports, which may include a variety ofinformation that demonstrates proper performance throughout the productshelf life. Some of the performance characteristics that must beprovided might include dose accuracy within an expected injection timethroughout the product shelf life.

Typically, a prefilled syringe containing the therapeutic fluid isdefined early in the development process. An auto injector is laterselected and an injection time of the prefilled syringe in the autoinjector has to meet an expected injection time. In order to meet theexpected injection time, injection time simulations are generally used.Injection time simulations are generally mathematical in nature andbased on the geometry of the prefilled syringe. The geometry of theprefilled syringe notably comprises the following parameters of needlelength, needle diameter, and barrel diameter. Such simulations are alsogenerally based on parameters of the drug such as viscosity. Theseparameters enable simulation of the hydrodynamic forces that the fluidapplies against the stopper. The Hagen-Poiseuille equation is an exampleof a formula that models hydrodynamic forces. Friction forces duringdelivery are generally approximated using step-wise functions tosimulate a constant break loose force in a start of injection period anda constant gliding force in the rest of injection period.

In practice, friction forces between the prefilled syringe's stopper andbarrel typically are considered as constant in injection timesimulations. The constant force is typically extrapolated from ameasured extrusion force on an empty prefilled syringe when the stopperis moved at a speed comparable with the speed corresponding to theexpected injection time. Some more complex simulations may estimatefriction forces using the formula:

F _(friction)=((2πμ_(oil) r _(b) l _(stopper))/d _(oil))υ  (1)

where μ_(oil) is the viscosity of the lubricant, r_(b) is the internalradius of the syringe barrel, l_(stopper) is the length of the stopperin contact with the syringe barrel, d_(oil) is the thickness of thelubrication, and υ is the injection speed (linear piston speed withdimensions of length over time).

In general, for Newtonian fluids, neglecting the pressure drop acrossthe syringe barrel, the hydrodynamic force can be estimated at a giventemperature using the Hagen-Poiseuille equation:

F _(hydrodyamic)=((8πμL _(n) r _(b) ⁴)/r _(n) ⁴)υ  (2)

where μ is the viscosity of the fluid, L_(n) is the length of the needlechannel, r_(b) is the internal radius of the syringe barrel, and r_(n)is the internal radius of the needle channel.

Injection time simulations also are generally based on features of theauto injector, such as a dispensing force applied by the auto injectoron the stopper of the prefilled syringe barrel. The dispensing force isbased on the parameters and configuration of the auto injector'sinjection spring or other structure that powers movement of the autoinjector's injection mechanism. Potential resistive forces internal tothe auto injector may also be taken into account.

By calculating the forces applied to the stopper using these variousmathematical models, an injection time to fulfill injection can besimulated. The simulated injection time then can be used to confirmwhether the parameters and configuration of the injection spring willprovide enough dispensing force against the stopper to satisfy theexpected injection time.

SUMMARY

In general terms, this patent document is directed to determining aspring for an auto injector. Another aspect is directed to determiningan auto injector having a determined spring.

One aspect of this patent document is a method of making an autoinjector. The method comprising aging a prefilled syringe, the prefilledsyringe having a stopper, measuring a force required to move the stopperwithin the aged prefilled syringe a determined distance within adetermined time, and selecting a spring having a determined springforce, the determined spring force moving the stopper the determineddistance within the determined time.

One aspect of this patent document is a method of making an autoinjector to dispense a therapeutic fluid contained in an operativeprefilled syringe, the operative prefilled syringe including anoperative barrel and an operative stopper movably positioned within theoperative barrel, the operative stopper movable along an operative pathof travel from a first operative position to a second operativeposition, the auto injector to comprise an injection spring having aspring force, the injection spring configured to apply a dispensingforce to the operative stopper by driving a piston rod toward theoperative stopper upon actuation of the auto injector, the dispensingforce being at least a portion of the spring force. The method comprisesaging a prefilled syringe at an accelerated rate to form a referenceprefilled syringe, the reference prefilled syringe including a referencebarrel and a reference stopper positioned in the reference barrel;moving the reference stopper of the reference prefilled syringe along areference path of travel from at least a first reference position to atleast a second reference position; as the reference stopper moves withinthe reference barrel along the reference path of travel, measuring aplurality of exertion forces applied to the reference stopper andmeasuring a plurality of reference stopper positions; generating anexertion force profile, the exertion force profile including at leastsome of the exertion forces and reference stopper positions measuredwhile the reference stopper was moving between the first and secondreference positions, at least one of the measured exertion forcescorrelating to at least one of the measured reference stopper positions;and selecting the injection spring so that the dispensing force appliedto the operative stopper at each position of the operative stopper as itmoves along the operative path of travel between the first and secondoperative positions is greater than the measured exertion force at acorresponding one of the measured reference stopper positions.

Another aspect of this patent document also relates to an auto injectorhaving an aged prefilled syringe, a stopper within the prefilledsyringe, and an injection spring. The injection spring having a springforce with a magnitude great enough to move the stopper a determineddistance.

Another aspect of this patent document is an auto injector arrangementcomprising a prefilled syringe including a barrel extending along alongitudinal axis between a distal end and a proximal end, an innerdiameter of the barrel being of about 8.65 mm, a needle disposed at thedistal end of the barrel, the needle having an inner diameter of about0.27 mm and a length of about 19.5 mm or less, a volume in the rangefrom about 1.51 mL to about 1.66 mL of therapeutic fluid held within thebarrel, the therapeutic fluid comprising fremanezumab, a viscosity ofthe therapeutic fluid being about 8.8 cSt at 22° C., and a stopperdisposed within the barrel to retain the therapeutic fluid within thebarrel, the barrel defining a path of travel for the stopper, the pathof travel having a first initial position for the stopper and a secondinitial position for the stopper, the first position being an initialposition of the stopper before delivery of the therapeutic fluid, thesecond position being a final position of the stopper upon delivery of afull dose of the therapeutic fluid. An auto injector holds the prefilledsyringe. The auto injector comprises an injection spring arranged toapply a dispensing force to the stopper by driving a piston rod towardthe stopper. When the auto injector is actuated, the injection spring isconfigured to provide an initial dispensing force to the stopper of atleast about 20 N when the stopper is positioned at the first initialposition and a final dispensing force of at least 12 N to the stopperwhen the stopper is positioned at the second final position, thedispensing force being at least a portion of a spring force for theinjection spring.

Another aspect of this patent document also relates to an auto injectorhaving an aged prefilled syringe, a stopper within the prefilledsyringe, and an injection spring. The injection spring having a springforce with a magnitude great enough to move the stopper a determineddistance within a determined time.

Another aspect of this patent document is an auto injector arrangementcomprising a prefilled syringe. The prefilled syringe comprises a barrelformed at least in part by glass, a needle in fluid communication withthe barrel, and a stopper positioned in the barrel, the barrel definingan inner surface, the barrel having an inner diameter, the barreldiameter being about 8.65 mm, the barrel defining a path of travel forthe stopper, the path of travel having a first position for the stopperand a second position for the stopper, the needle having an innerdiameter of about 0.27 mm and a length of about 19.5 mm or less, atherapeutic fluid held within the barrel, a viscosity of the therapeuticfluid being about 10 cP or less at 22° C. About 0.35 mg to about 1.1 mgof silicone oil lubricates the inner surface of the barrel, the siliconeoil having a viscosity in a range from about 500 cSt at 25° C. to about1500 cSt at 25° C. before the prefilled syringe is aged. An autoinjector holds the prefilled syringe. The auto injector comprises aplunger and an injection spring. The plunger engages the stopper, andthe injection spring biases the plunger towards the stopper. Theinjection spring, when in the first position, has a force determinedaccording to the actions recited in claim 1; has a spring force in therange from about 20 N to about 30 N; has a stored spring energy in therange from about 0.9 J to about 2 J; has a spring constant in the rangefrom about 0.2 N/mm to about 0.4 N/mm; a compressed length in the rangefrom about 50 mm to about 100 mm; has a stored energy about 25% greaterthan a minimum spring energy required to move the stopper from the firstposition to the second position without stalling before the prefilledsyringe is aged; and has a force sufficient to move the stopper alongthe path of travel from the first position to the second position withinabout 5 seconds to about 25 seconds.

Another aspect of this patent document also relates to an auto injectorhaving an aged syringe prefilled with fremanezumab, a stopper within theprefilled syringe, and an injection spring. The injection spring havinga spring force with a magnitude great enough to move the stopper adetermined distance.

Another aspect of this patent document is a prefilled syringe comprisinga stopper and a therapeutic fluid including fremanezumab; and an autoinjector having an injection spring and a piston rod arranged to movethe stopper from a first position to a second position with a force ofabout 30 N or less and in about 19 seconds or less, the distance betweenthe first and second positions corresponding to one dose of thetherapeutic fluid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of an example syringe prefilled with afluid in accordance with the principles of the present disclosure;

FIG. 2 shows sequence listings for fremanezumab, which can be loaded inthe prefilled syringe shown in FIG. 1;

FIG. 3A is a graph plotting one set of measured exertion forces againstdisplacement of the drive member acting on a stopper of an unagedprefilled syringe;

FIG. 3B is a chart showing maximum exertion force measured for prefilledsyringes of various artificial ages;

FIG. 3C is a graph plotting one set of measured exertion forces againstdisplacement of the drive member acting on a stopper of a prefilledsyringe artificially aged to 24 months;

FIG. 3D is a chart showing injection times observed for prefilledsyringes of various natural and artificial ages;

FIG. 4A is a side elevational view in partial cross-section showing afixture for testing a prefilled syringe;

FIG. 4B is a side elevational view in partial cross-section showing analternative fixture for testing a prefilled syringe and auto injectormechanism;

FIG. 4C is a side cross-sectional view of a fixture for testing springforces in an auto injector;

FIG. 5 is a side elevational view of an instrument for measuringperformance of prefilled syringes and auto injectors for use with thefixtures illustrated in FIGS. 4A-4C;

FIG. 6 is a flowchart illustrating a determination process by which aspring constant can be selected for the injection spring of an autoinjector;

FIG. 7 is a schematic diagram of an example oven used in artificiallyaging one or more prefilled syringes;

FIGS. 8-10 illustrate various testing processes that are each suitablefor implementing the test operation of the determination process of FIG.6;

FIG. 11 is a flowchart illustrating a method for performing at least themove operations and the measure operations of the testing processes ofFIGS. 8-10 using the testing equipment of FIG. 5;

FIG. 12 is a flowchart illustrating an assembly process for assemblingan auto injector;

FIG. 13 illustrates the components of the auto injector exploded fromeach other for ease in viewing;

FIG. 14 is a cross-section of the auto injector of FIG. 13, the autoinjector being disposed in a pre-injection configuration;

FIG. 15 shows the auto injector of FIG. 14 in a mid-injectionconfiguration;

FIG. 16 shows the auto injector of FIG. 14 in an end of injectionconfiguration;

FIG. 17 shows the auto injector of FIG. 16 rotated 90°;

FIG. 18 is a flowchart illustrating a use process for using the autoinjector with the prefilled syringe and the selected injection spring;and

FIG. 19 illustrates the auto injector being actuated by a user.

DETAILED DESCRIPTION

Various embodiments will be described in detail with reference to thedrawings, wherein like reference numerals represent like parts andassemblies throughout the several views. Reference to variousembodiments does not limit the scope of the claims attached hereto.Additionally, any examples set forth in this specification are notintended to be limiting and merely set forth some of the many possibleembodiments for the appended claims.

For purposes of this patent document, the terms “or” and “and” shallmean “and/or” unless stated otherwise or clearly intended otherwise bythe context of their use. Whenever appropriate, terms used in thesingular also will include the plural and vice versa. The use of “a”herein means “one or more” unless stated otherwise or where the use of“one or more” is clearly inappropriate. The use of “or” means “and/or”unless stated otherwise. The use of “comprise,” “comprises,”“comprising,” “include,” “includes,” “including,” “having,” and “has”are interchangeable and not intended to be limiting. The term “such as”also is not intended to be limiting. For example, the term “including”shall mean “including, but not limited to.”

All ranges provided herein include the upper and lower values of therange unless explicitly noted. Although values are disclosed herein whendisclosing certain exemplary embodiments, other embodiments within thescope of the pending claims can have values other than the specificvalues disclosed herein or values that are outside the ranges disclosedherein.

Terms such as “substantially” or “about” when used with values orstructural elements provide a tolerance that is ordinarily found duringtesting and production due to variations and inexact tolerances infactor such as material and equipment. These terms also provide atolerance for variations found in nature and environmental conditionsdue to factors such as changes in temperature, humidity.

As used herein, the term “fremanezumab” is used interchangeably to referto an anti-CGRP antagonist antibody produced by expression vectorshaving deposit numbers of ATCC PTA-6867 and ATCC PTA-6866. The aminoacid sequence of the heavy chain and light chain variable regions areshown in SEQ ID NOs: 1 and 2, respectively. The CDR amino acid sequencesof the G1 heavy chain variable region are shown in SEQ ID NOs: 7-9(Kabat and Chothia CDRs are indicated). The CDR amino acid sequences ofthe G1 light chain variable region are shown in SEQ ID NOs: 10-12.Exemplary polynucleotides encoding the G1 heavy and light chain variableregions are shown in SEQ ID NO: 5 and SEQ ID NO: 6, respectively. The G1heavy chain full length amino acid sequence is shown in SEQ ID NO: 3.The G1 light chain full length amino acid sequence is shown in SEQ IDNO: 4. Exemplary polynucleotides encoding the G1 full length heavy chainand light chains are shown in SEQ ID NO: 3 and SEQ ID NO: 4,respectively. The characterization of G1 is described in PCT PublicationNo. WO 2007/054809 and WHO Drug Information 30(2): 280-1 (2016), whichare hereby incorporated by reference in its entirety.

FIG. 1 illustrates an example embodiment of a prefilled syringe 150suitable for holding a therapeutic fluid 160 for injection. Theprefilled syringe 150 includes a barrel 151, a needle 155, and a stopper157. The barrel 151 defines an interior 154 sized to hold apredetermined amount of the fluid 160 (e.g., at least one dose of thetherapeutic fluid). The fluid 160 is held within the interior 154 of thebarrel 151 between the stopper 157 and the needle 155. An example of asyringe that can be used for the prefilled syringe 150 is a 2.25 mLEZ-Fill syringe supplied by Ompi (Piombino Dese, Italy). Other types ofsyringes can be used and syringes from other manufacturers also can beused.

The barrel 151 extends between a distal end 152 and an open proximal end153. The prefilled syringe 150 also has a tip 161 at the distal end 152.The barrel 151 defines a proximally facing shoulder 151 a at the distalend 152 of the interior 154 that extends between the barrel 151 and thetip 161.

The syringe barrel 151 is configured to hold about 2.25 mL of fluid.However, other barrel sizes can be utilized. For example, the barrel 151can be sized to hold about 1 mL of fluid. In other embodiments, thebarrel 151 is sized to a volume of therapeutic fluid 160 in the rangefrom about 1 mL to about 3 mL, about 1 mL to about 2.5 mL, or about 2 mLto about 2.5 mL. Other embodiments of the prefilled syringe 150 can holdother volumes of therapeutic fluid 160.

Additionally, the syringe barrel 151 has an inner diameter or otherinner cross-dimension of about 8.65 mm. In alternative embodiments,however, the barrel 151 can have an inner diameter in the range fromabout 6 mm to about 10 mm, or from about 8.5 mm to about 8.8 mm. Yetother possible embodiments can have an inner diameter other than inthese ranges.

In certain examples, the syringe barrel 151 is formed from Borosilicateglass. In certain examples, the syringe barrel 151 is formed from clear,type I Borosilicate glass. For example, the syringe barrel 151 can becomposed of a mixture of SiO₂, B₂O₃, Al₂O₃, Na₂O, and CaO. In a morespecific example, the syringe barrel 151 is formed with 75% SiO₂, 10.5%B₂O₃, 5% Al₂O₃, 7% Na₂O, and 1.5% CaO. Alternative embodiments withother mixtures of these materials can be used to form the glass for thesyringe barrel 151. Other embodiments can use other types of glass oreven materials other than glass to form the syringe barrel 151. Forexample, the syringe barrel 151 can be formed with plastic. In at leastsome embodiments, the syringe barrel 151 is a Borosilicate glass barrelsupplied by Schott Corporation of Elmsford, N.Y. Syringe barrels 151from other manufacturers can be used.

The stopper 157 is axially moveable within the interior 154 of thebarrel 151 along a path of travel, P, in a distal direction. The stopper157 has a main body that is substantially cylindrical or otherwise has across-section shape similar to a cross-section of the inner surface 156for the barrel 151. The stopper 157 has one or more flanges or ribs 158that extend radially from the main body. Additionally, the stopper 157has a compressed state and an uncompressed state, the stopper 157 is inthe compressed state when it is inserted into the syringe barrel 151.

The main body of the stopper 157 has a first engagement surface 157 afacing an exterior of the prefilled syringe 150 in a proximal directionand a second engagement surface 157 b facing the fluid 160 containedwithin the barrel 151. The first engagement surface 157 a is flat andthe end of a piston rod (e.g., 107 of FIGS. 14-17) abuts the engagementsurface 157 a during use. In alternative embodiments, the firstengagement surface 157 a may include a threaded hole (not shown) orother connection structure (not shown) so that the stopper 157 can bethreaded onto or otherwise connected to the end of a piston rod in theauto injector. To move the stopper 157 distally within the syringebarrel 151, a dispensing force can be applied to the first engagementsurface 157 a of the stopper 157 to push the stopper 157 along the pathof travel, P. The main body of the stopper 157 has a length of about 7.7mm. In alternative embodiments, the stopper 157 may have a length in therange from about 7.3 mm to about 8.1 mm, or from about 7 mm to about 9mm. Alternative embodiments of the stopper 157 can have a length that islonger or shorter than these ranges. Additionally, the outer diameter ofthe main body for the stopper 157 when it is in the compressed state isabout 8.95 mm. In some alternative embodiments, the outer diameter ofthe main body is in the range from about 8.85 mm to about 9.05 mm, orfrom about 5.5 mm to about 9.5 mm. Alternative embodiments can have amain body with an outer diameter that is outside of these ranges.Additionally, the outer diameter is measured from the base of a flange158, across the main body to the base of the flange 158 on the oppositeside of the main body.

The plurality of annular flanges 158 engage the inner surface 156 of thesyringe barrel 151. The flanges 158 create a substantially air-tightseal against the inner surface 156 of the syringe barrel 151 and holdsthe therapeutic fluid 160 within the interior 154. The stopper 157includes four flanges 158. In alternative embodiments, the stopper 157may have a greater or lesser number of flanges 158. For example, thestopper 157 could have one flange, two flanges, three flanges, or morethan four flanges. Alternative embodiments might also include no flangesso that the entire outer surface 162 between the first and secondengagement surfaces 157 a, 157 b engages the inner surface 156 of thesyringe barrel 151. In the compressed state, the stopper 157 has anouter diameter or cross-dimension of about 8.95 mm. In alternativeembodiments, the outer diameter of the stopper 157 in the compressedstate may be in the range from about 6 mm to about 10 mm, or from about6.5 mm to about 9.5 mm. In some examples, the outer diameter of thestopper 157 is the outer diameter across the largest portion of thestopper 157 (e.g., across at least one of the flanges 158), and it is atleast slightly larger than the inner diameter or inner cross-dimensionof the syringe barrel 151 to ensure a seal between the two. When in theuncompressed state, at least some possible embodiments of the stopper157 have an outer diameter in the range from about 9.25 mm to about 9.45mm.

The stopper 157 is formed from a rubber such as Bromobutyl rubber,although materials other than rubber or other than Bromobutyl can beused to form the stopper 157. An example formulation that can be used toform the Bromobutyl rubber, such as the formulation 4023/50/GREY fromWest Pharmaceutical Services, PA, USA. Other formulations are possible.In other embodiments, material other types of rubber or material otherthan rubber is used to form the stopper 157. Additionally, the stopper157 can have a fluoropolymer coating on its outer surface 162 or have alaminated outer surface 162. In an example, the coating can cover theentire outer surface 162 of the stopper 157. In an alternative example,the coating can cover some or all of the second engagement surface 157b, some or all of the flanges 158, some or all of the portions of theouter surface 162 that opposes the inner surface 156 of the syringebarrel 151, some or all of first engagement surface 157 a, orcombinations of these surfaces. An example of the fluoropolymer materialthat can be used to coat the stopper 157 is ethylene tetrafluoroethylene(ETFE). An advantage of coating the stopper 157 with fluoropolymer isthat it prevents absorption or adsorption of the therapeutic fluid 160.

Material other than fluoropolymer can be used to coat or laminate thestopper 157. An example of an alternative material is silicone.Alternatively, the stopper 157 can be coated or laminated with two ormore materials. For example, the stopper 157 can have fluoropolymercoating the portion of its surface that comes into contact with thetherapeutic fluid 160, and silicone oil coating the portion of itssurface that does not come into contact with the therapeutic fluid 160.The coatings on the stopper 157 can operate as a lubricant, provideincreased biocompatibility with the therapeutic fluid 160, preventabsorption or adsorption of the therapeutic fluid 160 or itsconstituents, or a combination of the foregoing. In yet otherembodiments, the stopper 157 does not have any type of coating orlamination.

In use, the second engagement surface 157 b of the stopper 157 pushesthe fluid 160 towards the needle 155 to expel the fluid 160 from theprefilled syringe 150. The stopper 157 is moved from a first position,D1, along a path of travel, P to a second position, D2, along the pathof travel, P. In an example embodiment, the first position, D1, is aposition adjacent to the fluid 160 before any amount of a dose of thetherapeutic fluid 160 is delivered, and the second position, D2, is thelocation of the second engagement surface 157 b upon completing deliveryof a complete dose of the therapeutic fluid 160. When in the secondposition, D2, the stopper 157 is directly adjacent or even touching theshoulder 151 a of the syringe barrel 151. In an alternative embodiment,there can be a gap or air bubble between the therapeutic fluid 160 andthe stopper 157 when the stopper 157 is in the first position, D1, orthe stopper 157 can be spaced from the shoulder 151 a of the syringebarrel 151 when the stopper 157 is in the second position, D2.

The path of travel, P, can be about 29.6 mm, which is sometimes referredto as a “30 mm” path of travel. In alternative embodiments, the path oftravel, P, can be in the range from about 25.7 mm to about 28.2 mm, fromabout 25 mm to about 29 mm, or from about 25 mm to about 40 mm. In someembodiments, the path of travel, P, can be 29.6 mm. In otherembodiments, the length of the path of travel, P, can be a distanceoutside these ranges. A volume of therapeutic fluid 160 in the prefilledsyringe 150 that is held in the prefilled syringe 150 between the firstand second positions D1, D2 of the stopper 157 is about 1.585 mL, whichcorresponds directly to the interior volume of the syringe barrel 151between the first and second positions D1, D2. In alternativeembodiments, the volume of fluid 160 between the first and secondstopper 157 positions D1, D2 is in the range from about 1.51 mL to about1.66 mL. Alternative embodiments can have different volumes of fluid 160between the first and second positions D1, D2 of the stopper 157. Thevolume of fluid 160 may correspond to one full dose of therapeutic fluid160, multiple doses of the therapeutic fluid 160, or a partial dose ofthe therapeutic fluid 160.

The force applied to the stopper 157 by the auto injector 140 is thedispensing force. The amount of dispensing force required to push thestopper 157 in the prefilled syringe 150 can vary due to a variety offactors. Examples of such factors include the lubrication 159, thesyringe geometry and material, the stopper geometry and material, thetherapeutic fluid 160 in the prefilled syringe 150, desired injectiontime, and other resistive forces that oppose movement of the stopper157. Additionally, because the stopper 157 is compressible, it canabsorb some of the dispensing force applied to it by the piston rod ofan auto injector 140. The selected injection spring would have to haveenough force to overcome this absorption if absorption becomessignificant enough to affect performance of the auto injector 140.

Lubrication 159 may be disposed along an inner surface 156 of the barrel151 to facilitate movement of the stopper 157 within the barrel 151. Thelubrication 159 is disposed between the inner surface 156 of the barrel151 and an outer contact surface 162 of the stopper 157 as the stopper157 moves along the path of travel P. The lubrication 159 reduces thefriction between the outer contact surface 162 of the stopper 157 andthe inner surface 156 of the barrel 151.

The lubricant used to form the layer of lubrication 159 is a siliconeoil. An example of silicone oil that can be used is polydimethylsioxane.In alternative embodiments, a lubricant other than silicone oil, asilicone oil other than polydimethylsioxane, or any other suitablelubricant is used to lubricate the inner surface 156 of the barrel 151.The lubrication 159 can cover the entire inner surface 156 of thesyringe barrel 151 including the wall of the barrel 151 and the shoulder151 a. In other examples, the lubrication 159 covers less than theentire inner surface 156 of the prefilled syringe 150 such as only alongthe wall of the barrel 151, or only along those portions of the wall ofthe barrel 151 that extend along the path of travel, P.

In at least some embodiments, the layer of lubrication 159 has asubstantially uniform thickness along the path of travel P.Alternatively, the layer of lubrication 159 has a substantially uniformthickness along substantially the entire length of the syringe barrel151. Additionally, in at least some embodiments, the layer oflubrication 159 has a substantially uniform thickness around the innercircumference of the syringe barrel 151. In other embodiments, thethickness of the layer of lubrication 159 varies over the length of thesyringe barrel 151 or along the path of travel P. For example, thethickness of the lubrication 159 can gradually thin toward the distalend 152 of the prefilled syringe 150 compared to the proximal end 153 ofthe prefilled syringe 150. As discussed in more detail herein, thethickness of the lubrication 159 can have other variations and also cancarry around the circumference of the syringe barrel 151.

In possible embodiments, the thickness of the lubrication layer 159 isabout 0.5 μm. Other thicknesses are possible. For example, thelubrication layer 159 may have a thickness between about 0.1 μm andabout 1 μm along the path of travel, P. In other examples, thelubrication layer 159 may have a thickness between about 0.1 μm andabout 0.3 μm along the path of travel, P.

In at least some embodiments, the prefilled syringe 150 includes about0.7 mg of silicone oil to form the lubricating layer 159. In otherembodiments, the amount of silicone oil is in the range from about 0.4mg to about 1.1 mg. In yet other embodiments, the amount of silicone oilis in the range from about 0.35 mg to about 1.0 mg.

In an example embodiment, the lubricant forming the lubrication layer159 has a viscosity of about 1000 cSt at 25° C. In an alternativeembodiment, the lubricant has a viscosity in the range from about 500cSt to about 1000 cSt at 25° C., from about 100 cSt to about 1000 cSt at25° C., or less than about 1250 cSt at 25° C. In yet other embodiments,the lubricant has a viscosity outside of these ranges.

The needle 155 is disposed at the distal end 152 of the barrel 151 andis connected to the tip 161. The needle 155 is secured to the tip 161with an adhesive. In alternative embodiments, the needle 155 isconnected to the tip 161 using a hub or other structure.

The needle 155 extends between a first end and a second end. The needle155 is connected to the distal end 152 of the syringe barrel 151 at oradjacent to the first end of the needle 155. The second end of theneedle 155 may be sufficiently sharp or pointed to assist in breakingskin 192 at an injection site 198 of a user 190 (see FIG. 19). Theneedle 155 defines a channel 155 a that is in fluid communication withthe interior 154 of the prefilled syringe 150. In operation, fluid 160flows through the channel 155 a to exit the syringe barrel 151. Thechannel 155 a of the needle 155 has an internal diameter orcross-dimension, which is the distance from one point on the peripheryto another point on the opposite side of the periphery. An internaldiameter is an example of the cross-dimension when the channel 155 a iscircular in cross-section. In an example, the channel 155 a has aconstant internal diameter or cross-dimension along a length of theneedle 155. In other embodiments, however, the internal diameter orcross-dimension can vary along the length of the channel 155 a.

The needle 155 is a stainless steel needle such as a Grade AISI 304stainless steel needle supplied by Chirana T. Injecta of Slovakia.Additionally, the needle 155 has an ISO-name 4301-304-00-1 and an ISOdesignation X5CrNi18-9. Other materials can be used to form the needle155. Other embodiments can use needles 155 from other manufacturers, andneedles 155 having alternative ISO certifications or no certification atall.

The needle 155 has a length of 19.5 mm. In alternative embodiments, theneedle 155 can have a length in the range from about 15 mm to about 25mm, from about 18.3 mm to about 20.7 mm, or less than 19.5 mm. Otherembodiments can have a needle length that is longer or shorter thanthese ranges. Additionally, the needle channel 155 a has an innerdiameter or inner cross-dimension of 0.27 mm, from about 0.15 mm toabout 0.3 mm, from about 0.25 mm to about 0.29 mm, from about 0.21 mm toabout 0.3 mm, or less than 0.27 mm. In other embodiments, the needle 155has an inner diameter of about 0.29 mm or less. Other embodiments havean inner diameter that is narrower or wider than these ranges.

The therapeutic fluid 160 can contain drugs having pharmacological orother active ingredients, biologics, biosimilars, or any othercomposition for treating a body. Depending on the composition of thetherapeutic fluid 160 and prescribed treatment, the therapeutic fluid160 can have one of a variety of different volumes and viscosities. Inat least some possible embodiments, for example, the therapeutic fluid160 has a volume of about 1.585 mL. In other embodiments, the volume oftherapeutic fluid 160 is in the range from about 1.51 mL to about 1.66mL. In other embodiments, the volume of therapeutic fluid 160 is in therange from about 1 mL to about 2.25 mL. Yet other embodiments have othervolumes of therapeutic fluid 160 loaded in the prefilled syringe 150.

The therapeutic fluid 160 may be a liquid pharmaceutical compositioncomprising fremanezumab, disodium ethylenediaminetetraacetic aciddihydrate (EDTA), L-histidine, L-histidine hydrochloride monohydrate,polysorbate-80, sucrose, and water for injection. An example of aparticular formula for the therapeutic fluid 160 is about 225 mgfremanezumab, about 0.204 mg disodium ethylenediaminetetraacetic aciddihydrate (EDTA), about 0.815 mg L-histidine, about 3.93 mg L-histidinehydrochloride monohydrate, about 0.3 mg polysorbate-80, about 99 mgsucrose, and water for injection at a pH of about 5.5. In an alternativeembodiment, the therapeutic fluid 160 can be formulated at 150 mg/mLnominal concentration in 16 mM histidine, 6.6% sucrose, 0.136 mg/mLEDTA, 1.2 mg/mL P580, pH 5.5. In some embodiments, at least about 70% ofthe fremanezumab in the liquid pharmaceutical composition is of theIgG2-B disulfide isoform. In some embodiments of any of the compositionsprovided herein, about 72% of the antibody molecules in the compositionare of the disulfide isoform B, wherein about 22% of the antibodymolecules in the composition are of the IgG2-A/B, and wherein about 6%of the antibody molecules in the composition are of the IgG2-A disulfideisoform. Other embodiments of the therapeutic fluid 160, including thosefor fremanezumab, can have other formulations including otherconstituents. Additionally, the therapeutic fluid 160 can have drugs,biologics, or biosimilars other than fremanezumab.

The viscosity of the liquid pharmaceutical composition may be about 8.8cSt at 22° C. Other viscosities are possible. For example, thetherapeutic fluid 160 may have a viscosity ranging from about 4 cSt at22° C. to about 14 cSt at 22° C. In certain examples, the therapeuticfluid 160 has a viscosity ranging from about 8 cP at 22° C. to about 10cP at 22° C. In certain examples, the therapeutic fluid 160 has aviscosity less than about 10 cSt at 22° C.

The therapeutic fluid 160 can be used for the treatment or prevention ofa variety of different temporary or chronic diseases, conditions, orother maladies. The therapeutic fluid 160 can be used for the treatmentor prevention of any disease or disorder associated with CGRP(Calcitonin Gene-Related Peptide) activity or CGRP upregulation. In onepossible embodiment, the therapeutic fluid 160 comprises a biologic suchas for treating episodic or chronic migraine headaches. For example, thetherapeutic fluid 160 can include an immunoglobulin G₂ (IgG2) monoclonalantibody. In another example, the therapeutic fluid 160 includes ahumanized IgG2 monoclonal antibody. The antibody also may be expressedin CHO cells. In another example, the therapeutic fluid 160 includes ananti-CGRP protein.

In a more specific example, and with reference to FIG. 2, thetherapeutic fluid 160 includes an antibody comprising a heavy chainvariable region V_(H) domain that is at least 90%, optionally 95%, 97%,99%, or 100% identical in amino acid sequence to SEQ ID NO: 1 and alight chain variable region V_(L) domain that is at least 90%,optionally 95%, 97%, 99%, or 100% identical in amino acid sequence toSEQ ID NO: 2. In certain examples, the therapeutic fluid 160 includesthe antibody produced by the expression vectors with ATCC Accession Nos.PTA-6867 and PTA-6866. In another example, the therapeutic fluid 160includes fremanezumab.

In other examples, the therapeutic fluid 160 includes an antibodycomprising the following CDRs: CDR H1 as set forth in SEQ ID NO: 3; CDRH2 as set forth in SEQ ID NO: 4; CDR H3 as set forth in SEQ ID NO: 5;CDR L1 as set forth in SEQ ID NO: 6; CDR L2 as set forth in SEQ ID NO:7; and CDR L3 as set forth in SEQ ID NO: 8.

The therapeutic effects of fremanezumab are long lasting and can betaken by injection relatively infrequently. In one embodiment, forexample, fremanezumab can be administered about one time per month orless frequently. In another example, fremanezumab can be administeredabout once every two months or less frequently. In another example,fremanezumab can be administered about once every three months or lessfrequently. In another example, fremanezumab can be administered aboutonce every four months or less frequently. Fremanezumab is disclosed inmore detail in U.S. Pat. No. 8,007,794, which issued on Aug. 30, 2011,and is entitled “Antagonist Antibodies Directed Against CalcitoninGene-Related Peptide and Methods Using the Same”, the entire disclosureof which is hereby incorporated herein by reference.

The therapeutic fluid 160 also can be used for the treatment orprevention of other conditions such as cluster headaches, posttraumaticheadaches, fibromyalgia, and Interstitial Cystitis/Bladder Pain Syndrome(ICBPS).

In certain implementations, the therapeutic fluid 160 is expected tohave a shelf life of about 24 months when stored between 2° C. and 8° C.In an example, the therapeutic fluid 160 is expected to have a shelflife of about 2 years when stored at 5° C. In other embodiments, thetherapeutic fluid 160 is expected to have a shelf life of at least 12months when stored between 2° C. and 8° C. In certain examples, thetherapeutic fluid 160 is expected to have a shelf life of at least 18months when stored between 2° C. and 8° C. In certain examples, thetherapeutic fluid 160 is expected to have a shelf life of at least 30months when stored between 2° C. and 8° C. In certain examples, thetherapeutic fluid 160 is expected to have a shelf life of at least 36months when stored between 2° C. and 8° C. In certain examples, thetherapeutic fluid 160 is expected to have a shelf life of at least 6months when stored between 2° C. and 8° C. In certain examples, thetherapeutic fluid 160 is expected to have a shelf life of at least 9months when stored between 2° C. and 8° C.

It has been discovered that traditional injection time simulations forprefilled syringes 150 have several disadvantages. For example, severalaspects of a prefilled syringe 150 change over time and, given enoughtime, some of the changes can cause significant problems withperformance of the prefilled syringe 150 and an auto injector 140 inwhich the prefilled syringe 150 is mounted. Many of these changes arenot commonly taken into account by current injection time simulations,and can include changes to the prefilled syringe 150 that increaseresistive forces opposing movement of the stopper 157 within the syringebarrel 151.

The increase in resistive forces can be great enough to slow the speedof the syringe stopper 157 within the syringe barrel 151 compared to theprefilled syringe 150 before the changes occurred. Sometimes, the speedof injection due to these increased resistive forces may causediscomfort to the patient. The slow injection also could result in animpatient user 190, who is self-administering the therapeutic fluid 160,to pull the needle 155 out of their body prematurely, thereby resultingin an incomplete delivery of the fluid 160. In yet another embodiment,movement of the stopper 157 can even stall, resulting in delivery ofonly a partial dose.

Friction and hydrodynamic forces are examples of resistive forces thatoppose movement of the stopper 157 and may affect the break-loose forceand glide force, and thereby the injection time and dose accuracy. Thebreak-loose force is the amount of force required to set the stopper 157in motion, and the glide force is the amount of force required tosustain movement of the stopper 157. Friction can be between the stopper157 and the syringe barrel 151. Other types of friction also can opposemovement of the stopper 157. Hydrodynamic force is the force required topush the fluid 160 through the barrel 151, into the needle 155, and thenthrough the needle 155.

There are several changes that can occur over time and increase frictionbetween the stopper 157 and syringe barrel 151. For example, thelubrication 159 in the syringe barrel 151 or on the stopper 157 candegrade or breakdown, whether due to time or interaction with theconstituents of the therapeutic fluid 160. The degradation of thelubrication 159 can cause the viscosity of the lubrication 159 toincrease. The degradation also can cause the layer of lubrication 159 onthe barrel wall 156 to thin over time. Furthermore, the lubrication 159is a fluid and flows along the barrel wall 156 over time, which cancause variations in the thickness of the lubrication 159 resulting inareas of increased friction along the stopper's path of travel, P,because the layer of lubrication 159 thins or is gone entirely.

There also are several examples of changes that can increasehydrodynamic forces. For example, some therapeutic fluids 160 can changeover time. The therapeutic fluid 160 can aggregate or crystalize overtime forming larger clumps that can become stuck in the channel 155 a ofthe hypodermic needle 155. The blockage created by these clumps mayincrease the hydrodynamic force required to move the fluid 160 throughthe needle 155. The result is greater resistance against movement of thestopper 157.

If a developer of therapeutic fluids or prefilled syringes wants to useactual, real world data to design an auto injector or to use forregulatory approval, they may choose to test a prefilled syringe thathas been aged at least as long as its desired shelf life. A problem withusing actual, real world data is that many therapeutic fluids andprefilled syringes are expected to have a long shelf life, some as longas 24 months or even longer.

Waiting this long to submit an application for regulatory approval of adrug delivered by an auto injector until after the natural shelf life ofthe therapeutic fluid lapses can significantly delay the approvalprocess for the medication and the time at which the pharmaceuticalcompany can put the therapeutic fluid on the market. As a result,potentially life-altering or even life-saving medications are delayed inreaching patients. In addition, this delay makes it more difficult forthe pharmaceutical company to recover the huge investment required toresearch and find a successful medication. To speed up the regulatoryapproval process, the pharmaceutical companies may use simulated oraccelerated aging to replicate the effects of time. For example, thepharmaceutical company can use mathematical modeling to approximate theperformance of a prefilled syringe after a certain period of time. Inanother example, the pharmaceutical companies heat the prefilled syringeat a determined temperature and for a determined period of time tosimulate aging. The relationship between the length of time heating theprefilled syringe and the actual, non-accelerated length of time can bedefined according to the Arrhenius calculation:

K=Ae ^(−EA/(RT))  (3)

where “K” is the rate constant, “T” is the absolute temperature (inKelvin), “Ae^(−EA)” are constants for a given reaction, and “R” is auniversal gas constant.

It was discovered that artificial aging of the prefilled syringes 150 orthe therapeutic fluid 160 can lead to complications during stabilitytesting. For example, during stability testing using artificial aging,it was discovered that the combination of an aged prefilled syringe 150and an auto injector (e.g., the auto injector 140 shown in FIGS. 13-17)could result in various operation failures, including failure to injectwithin the intended injection time. It was further discovered thatartificial aging of the prefilled syringe 150 led to higher thanexpected resistive forces on the stopper 157. For example, the resistiveforce exerted on the stopper 157 towards the end of an injection strokealong the path of travel, P, was higher than expected. Accordingly, theinjection spring 109 used in a standard auto injector device was notable to consistently successfully operate the auto injector with theartificially aged prefilled syringe 150 as the simulated agingincreased.

In particular, it was discovered that heating the prefilled syringe 150exaggerates certain changes that occur over time. For example, heatingcauses changes to the prefilled syringe 150 to occur faster than theywould during an equivalent amount of time for natural aging. Forexample, when compared to a prefilled syringe 150 that is naturally agedat a non-accelerated rate for 24 months, a prefilled syringe 150 subjectto accelerated aging by heating for a simulated 24-month period willshow changes of a greater magnitude or even more types of changes, suchas changes to the thickness of the lubricating layer 159, greaterdecreases to the viscosity of the lubricant, greater variations in thethickness of the lubricating layer 159, more interaction between thetherapeutic fluid 160 and the lubricant, and the like.

All of these exaggerated changes that occur during artificial oraccelerated aging unnaturally increase friction and hydrodynamic forcesas compared to a prefilled syringe 150 that ages naturally. When anartificially aged prefilled syringe 150 having increased resistance tomovement of the stopper 157 is combined with an auto injector (e.g., theauto injector 140 described in more detail herein), there can beoperational failures including failure to inject the therapeutic fluid160 within the intended injection time or even injection stalls. Yet thepharmaceutical company must show data that the auto injector 140 canmove the stopper 157 to deliver a full dose of the therapeutic fluid 160within a reasonable period of time and not stall. To enable an effectiveregulatory path by allowing artificial aging and meeting stabilityrequirements, it is herein proposed to adapt the auto injector 140. Aninjection spring 109 for the auto injector 140 that has enough springforce to meet acceptable delivery specifications for an artificiallyaged prefilled syringe 150 is used. However, it is noted that theprefilled syringes used in the auto injectors on the market will benaturally aged. Further, it is noted that increasing unnecessarily thespring force is generally not beneficial because it may lead to somediscomfort, bruising of the patient, or breakage of the prefilledsyringe.

An example of this problem with artificially aged prefilled syringes 150is illustrated in the charts shown in FIGS. 3A-3D. To generate the datashown in FIGS. 3A-3D, the prefilled syringes 150 used were 2.25 mLEZ-Fill syringes with an internal barrel diameter of about 8.65 mmsupplied by Ompi of Piombino Dese, Italy, the stopper 157 was a FluroTecplunger from West Pharmaceutical Services, PA of Exton, Pa., USA, andthe needle 155 was a Grade AISI 304 stainless steel needle supplied byChirana T. Injecta of Slovakia with an internal diameter of about 0.27mm and a length of about 19.5 mm. The syringe barrels 151 werelubricated with 0.7 mg of silicone oil having a viscosity of about 1000cSt at 25° C. The therapeutic fluid 160 loaded in the prefilled syringes150 consisted of about 1.585 mL of a formulation of fremanezumabformulated at 150 mg/mL nominal concentration in 16 mM histidine, 6.6%sucrose, 0.136 mg/mL EDTA, and 1.2 mg/mL P580 at a pH of 5.5. Thetherapeutic fluid 160 had a viscosity of 8.8 cSt at 22° C. Multipleunaged prefilled syringes 150 were tested. The path of travel, P, of thestopper 157 in the barrel 151 corresponding to the extrusion of thetherapeutic fluid 160 is of about 30 mm.

FIG. 3A is a graph plotting the force exerted against the syringestopper 157 of an unaged prefilled syringe 150 versus displacement ofthe stopper 157 when the stopper 157 is moved at a constant speed. Thegraph may be obtained using the test equipment described with referenceto FIGS. 4A and 5. The y-axis shows the force exerted against thestopper 157 measured in Newton, N. Because the stopper 157 is moved at asubstantially constant speed, this exertion force is substantially equalto the resistive force that acts against movement of the stopper 157.The displacement is the displacement from a first (initial) position ofthe stopper 157 at the beginning of an injection and a second (final)position of the stopper 157. The chart in FIG. 3A shows the maximumresistance force during movement of the stopper 157 is about 8 N untiljust before the displacement reaches about 30 mm, which corresponds tothe stopper 157 reaching and hitting the shoulder 151 a in the syringebarrel 151.

FIG. 3B is a bar chart showing the maximum force exerted on the stopper157 of a prefilled syringe 150 subjected to accelerated aging. Theprefilled syringes 150 exposed to accelerated aging were heated at 40°C. for a period of time equivalent to simulate a desired natural age.For each prefilled syringe 150, the stopper 157 was pressed forextruding the therapeutic fluid 160 at a constant speed and the forceexerted against the stopper 157 was measured. The force exerted againstthe stopper 157 is equivalent to or corresponds to the force resistiveto movement of the stopper 157. The graph was obtained using the testequipment described with reference to FIGS. 4A and 5. The y-axis showsthe maximum force exerted against the syringe stopper 157 in Newtonwhile it is moved to deliver a dose of therapeutic fluid 160 at aconstant speed. The x-axis shows the simulated age of the prefilledsyringe 150 after it goes through accelerated aging. The first bar showsthe maximum exertion force before accelerated aging. The second barshows the maximum exertion force for a prefilled syringe 150 that has asimulated age of 3 months (T3). The third bar shows the maximum exertionforce for a prefilled syringe 150 that has a simulated age of 6 months(T6). The fourth bar shows the maximum exertion force for a prefilledsyringe 150 that has a simulated age of 9 months (T9). The fifth barshows the maximum exertion force for a prefilled syringe 150 that has asimulated age of 14 months (T14). The sixth bar shows the maximumexertion force for a prefilled syringe 150 that has a simulated age of24 months (T24).

As can be seen, the maximum force measured while moving the stopper 157during testing gradually increases to about 14 N, which is much greaterthan the 8 N measured for an unaged prefilled syringe 150. Each bar onthe chart represents a group of prefilled syringes 150 tested at eachsimulated age and shows the range of measured exertion forces for thegroup from the highest maximum exertion force measured to the lowestmaximum exertion force measured for the group. Each bar also presents abox representing the middle two quartiles or the middle 50% of themeasured exertion forces.

FIG. 3C is a graph plotting the force exerted against the syringestopper 157 of a prefilled syringe 150 having a simulated age of 24months versus displacement of the stopper 157. The prefilled syringes150 exposed to accelerated aging were heated at 40° C. for a period oftime equivalent to simulate a desired natural age. For each prefilledsyringe 150, the stopper 157 was pressed for extruding the therapeuticfluid 160 at a constant speed and the force exerted against the stopper157 was measured. The force exerted against the stopper 157 isequivalent to or corresponds to the force resistive to movement of thestopper 157. The y-axis shows the force exerted against the stopper 157measured in Newton, N. The graph was obtained using the test equipmentdescribed with reference to FIGS. 4A and 5. Because the stopper 157moves at a substantially constant speed, this exertion force issubstantially equal to the resistive force that acts against movement ofthe stopper 157. The displacement is the displacement from a firstposition of the stopper 157 at the beginning of an injection and theending position of the stopper 157. The chart in FIG. 3C shows themaximum resistance force during movement of the stopper 157 is about 14N until just before the displacement reaches 30 mm, which corresponds tothe stopper 157 reaching and hitting the shoulder 151 a in the syringebarrel 151.

As can be seen in FIGS. 3B and 3C, the peak or maximum force required tomove the stopper 157 a distance of 30 mm for a prefilled syringe 150that had a simulated or accelerated age of 24 months was in the rangefrom about 13 N to about 14 N. The peak force for the accelerated agedprefilled syringe 150 is in sharp contrast to the only 8 N to 9 N peakforce required to move the stopper 157 of the naturally aged prefilledsyringe 150 as shown in FIG. 3A. These charts show a significantincrease in the force required to move the stopper 157 for anartificially aged prefilled syringe 150 used in testing compared to anaturally aged prefilled syringe 150.

FIG. 3D is a bar chart showing injection time or how long it takes tomove the stopper 157 from the first position, D1, to the secondposition, D2, for prefilled syringes 150 subject to natural aging andprefilled syringes 150 subject to accelerated aging. The y-axis showsthe injection time in seconds, and the x-axis shows the age of theprefilled syringe 150. Data for naturally aged prefilled syringes 150 isshown with bars without a cross hatch, and data for accelerated agedprefilled syringes 150 is shown with bars with a cross hatch. Togenerate the data in FIG. 3D, an auto injector 140 with a prefilledsyringe 150 was mounted in a fixture, which held the auto injector 140upright with the needle 155 pointed down. A container was placed underthe auto injector 140 to collect fluid 160 as it was dispensed. The autoinjector 140 was actuated. A stopwatch was manually startedsimultaneously with actuating the auto injector 140 and stoppedimmediately when therapeutic fluid 160 stopped flowing from the needle155. A digital stop clock having an accuracy of within 100th of a secondwas used. Eight samples of naturally aged prefilled syringes 150 weretested at zero months, 1 month, 6 months, 9 months, 13 months, 19months, and 24 months. Four samples of accelerated aged prefilledsyringes 150 were tested at 12 months, 24 months, and 48 months. Eachbar on the chart represents a group of prefilled syringes 150 tested ata natural age or a simulated age as labelled on the chart and shows therange of injection time for each group from the longest injection timeto the shortest injection time. Each bar also presents a boxrepresenting the middle two quartiles or the middle 50% of the injectiontimes.

At 12 months, the naturally aged prefilled syringes 150 had an injectiontime in the range from about 18.6 s to about 20.8 s, whereas theaccelerated aged prefilled syringes 150 had an injection time in therange from about 16.4 s to about 39.3 s. At 24 months, the naturallyaged prefilled syringes 150 had an injection time in the range fromabout 18 s to about 21 s, whereas the accelerated aged prefilledsyringes 150 had an injection time in the range from about 19.4 s toabout 46.3 s. As can be seen, the delivery time for a naturally agedprefilled syringe 150 remains relatively steady throughout the life ofthe prefilled syringe 150. The delivery time for an artificially agedprefilled syringe 150 is comparable to the delivery time for a naturallyaged prefilled syringe 150 until the prefilled syringe 150 is about 9months old. After that age, the time for delivery of a full dose startsto rapidly increase for the artificially aged prefilled syringes 150. At24 months of simulated aging, the delivery time can reach more than 45seconds, which exceeds a target delivery time.

The above-described tests and results show that artificial aging of aprefilled syringe 150 can result in an increase in the force required tocomplete an injection. In certain cases, artificial aging of a prefilledsyringe 150 can result in an increase in the force required to completean injection within a desired or determined period of time (e.g., fromabout 5 seconds to about 19 seconds).

As a solution to these operation failures, the auto injector 140 may bemanufactured with an injection spring 109 that is sufficiently strong toaccommodate the higher extrusion forces on the stopper 157 of anartificially aged prefilled syringe 150. That is, the injection spring109 may need a sufficiently high spring constant K and compression toovercome the increased resistive forces generated by an artificiallyaged prefilled syringe 150, especially at the end of injection as thestopper 157 approaches the second position, D2, and the resistive forceis significantly greater than the resistive force at the beginning ofinjection, as can be seen in FIG. 3B. However, increasing the strengthof the injection spring 109 can lead to discomfort or even bruising ofthe patient. It also can lead to breakage of the syringe 150.Accordingly, using an injection spring 109 having more power thannecessary is undesirable.

The tests described below can be used in determining suitable springparameters for the injection spring 109 of an auto injector 140 used toinject therapeutic fluid 160 from an artificially aged prefilled syringe150. For example, the tests can determine a dispensing force that issufficiently strong to displace the syringe stopper 157 fully along theentire path of travel, P, within a predetermined time. The artificiallyaged prefilled syringe 150 used in these tests forms a referenceprefilled syringe 150 having a reference barrel 151, a reference stopper157, and a reference needle 155. The prefilled syringe 150 that isactually used in an auto injector 140 to deliver the therapeutic fluid160 to a patient is an operative prefilled syringe 150 having anoperative barrel 151, an operative stopper 157, and an operative needle155. The reference prefilled syringe 150 is substantially similar to theoperating prefilled syringe 150. To ensure proper performance of theoperative prefilled syringes 150, the reference prefilled syringes 150and the operative prefilled syringes 150 have substantially the samedimensions and are made from the same materials or materials thatprovide the same performance characteristics. In an alternativeembodiment, the reference prefilled syringes 150 and operative prefilledsyringes 150 can have different parameters. For example, the referenceprefilled syringe 150 can have parameters that provide more resistiveforce against movement of the stopper 157, which ensures that thedesigned injection spring 109 will still provide a suitable amount ofdispensing force throughout the entire range of spring compression sothat the auto injector 140 will inject a full dose of therapeutic fluid160 within the determined time.

FIGS. 4A and 4B illustrate a fixture for testing injection of prefilledsyringes 150 to determine an injection spring 109 having sufficientforce to meet performance criteria for regulatory approval of prefilledsyringes 150 and auto injectors 140. FIG. 4A illustrates a fixture 315for holding a prefilled syringe 150 and also illustrates the principlesof the test. The fixture 315 includes a syringe support frame 316 havinga bottom support 316 a, side supports 316 b, and a top plate 316 c. Thesyringe support frame 316 is of sufficient thickness and rigidness sothat it does not flex or compress under application of the forces usedin testing. The top plate 316 c defines a hole 316 d that is largeenough so the syringe barrel 151 will pass through the hole 316 d, butnot so large that the syringe flange 158 at the proximal end 153 of theprefilled syringe 150 will fit through the hole 316 d. In this way, theprefilled syringe 150 is supported by the top plate 316 c with theneedle 155 pointed down. A drive rod 314 is aligned with and has an endthat engages the first engagement surface 157 a of the syringe stopper157. A second, opposite end of the drive rod 314 is coupled to testingequipment configured to move the drive rod 314 at a substantiallyconstant speed. The drive rod 314 also is attached to measuringequipment such as a load cell 315 (see, e.g., FIG. 5) that is positionedto measure a force applied to the drive rod 314 as it moves.

The needle 155 is positioned in or above a collection container 318 tocollect the therapeutic fluid 160 as it is ejected from the prefilledsyringe 150. Collecting the therapeutic fluid 160 allows a comparison ofthe amount of fluid 160 loaded in the prefilled syringe 150 beforetesting to the amount of fluid 160 ejected from the prefilled syringe150 after testing to ensure a full dose is ejected during testing.Alternatively, the tip 161 of the needle 155 can be inserted into a massto simulate injection into a patient. Inserting the tip 161 of theneedle 155 into a mass enables the test apparatus to include theresistance to flow in its measurements of total resistance actingagainst movement of the syringe stopper 157. Examples of a mass that cansimulate an injection include cadaver tissue, animal tissue such as pig,and synthetic tissue.

During the test, the drive rod 314 is advanced or pushed against thestopper 157 to push the stopper 157 for a consistent speed and for adetermined distance. In at least some possible embodiments, thedetermined distance corresponds to the stopper 157 moving from the firstposition, D1, to the second position, D2, to deliver a full dose oftherapeutic fluid 160. The speed at which the drive rod 314 is pusheddownward is selected to simulate a desired timing for injection of theprefilled syringe 150 within an auto injector 140. In some embodiments,the drive rod 314 is advanced from the first position, D1, to the secondposition, D2, at a time in the range from about 5 s to about 12 s.

As the drive rod 314 is advanced against the syringe stopper 157, theload cell 315 measures the force applied to the drive rod 314 and therelative position of the drive rod 314 is measured. The displacement ofthe drive rod 314 will substantially equal the displacement of thesyringe stopper 157. The force measurements and the displacement of thedrive rod 314 at the time of each force measurement are recorded.

During testing, the force applied to the drive rod 314 to advance orpush the syringe stopper 157 is an exertion force, Fe. Forces thatoppose movement of the stopper 157 due to friction, hydrodynamics, andany force that resists movement of the stopper 157 is a resistive force,Fr. Because the stopper 157 moves at a substantially constant speedduring the test, the exertion force will substantially equal a resistiveforce. The exertion force may vary during advancement of the stopper 157due to changing resistive forces acting against movement of the stopper157.

FIG. 4B illustrates an alternative fixture 319 for testing prefilledsyringes 150 in combination with an auto injector 140. This embodimentis substantially similar to the fixture in FIG. 4A, and includes thesyringe support frame 316, which is supporting the prefilled syringe150. Additionally, a clamp 317 is mounted on the top plate 316 c of thesyringe frame 316 and includes first and second opposing jaws 317 a, 317b. Each of the first and second jaws 317 a, 317 b defines opposingcontours such as semicircular cutouts, which are shaped to receive andsecurely hold a portion of the auto injector 140 when the jaws 317 a,317 b are closed. In operation, an auto injector 140 has its injectionspring 109 removed and is mounted in the clamp 317 and is positioned sothe piston rod 107 from the auto injector 140 is axially aligned withthe syringe barrel 151. The piston rod 107 is inserted into the syringebarrel 151 so that the end of the piston rod 107 for the auto injector140 engages the first engagement surface 157 a of the stopper 157.

As described in more detail herein, the auto injector 140 includes asubassembly that moves in response to decompression of the injectionspring 109. The subassembly will include a structure for advancing thepiston rod 107. The subassembly also may include additional movingstructures and secondary spring mechanisms that also are moved or drivenby the injection spring 109 as it decompresses. In example embodiments,the entire auto injector 140, minus the injection spring 109, can bemounted in the clamp 317 provided there is access to insert the driverod 314 into the auto injector 140 so that it can engage and move thepiston rod 107 and other auto injector components that operate inresponse to movement of the piston rod 107. Alternatively, thesubassembly can be removed from the auto injector 140 or otherwiseexposed and mounted in the clamp 317 without components of the autoinjector 140 that are not operated by the injection spring 109.

The drive rod 314 connected to the test equipment engages and moves thepiston rod 107 at a constant speed for a determined distance. In atleast some embodiments, the determined distance corresponds to thedistance the stopper 157 is moving from the first position, D1, to thesecond position, D2, to deliver a full dose of the therapeutic fluid160. The exertion forces applied to the drive rod 314 and thedisplacement of the drive rod 314 are recorded. In this test setup, themeasured exertion force may correspond to the total resistance forceincluding friction in the prefilled syringe 150, hydrodynamic forces,friction in the subassembly, any force required to compress secondarysprings in the subassembly, and any other resistive force that actsagainst movement of the stopper 157 and movement of the subassembly.

FIG. 4C illustrates a fixture 320 for testing an auto injector 140 todetermine the spring strength for the injection spring 109. It is usedto simulate operation of the auto injector 140 and measure thedispensing force of the piston rod 107 as the injection spring 109decompresses. It is useful to verify proper operation of an autoinjector 140 after an injection spring 109 is selected as described inmore detail herein.

The fixture 320 includes a base 321 that can be secured to a workbench324 for stability during testing. The base 321 is secured to theworkbench 324 using bolts 326 a, 326 b. A tube 327 extends upward fromthe base 321 and defines a cavity 323 that is sized to receive an autoinjector 140. The length of the cavity 323 is about the same length ofthe housing 104 for the auto injector 140, although in variousembodiments it can be longer or shorter. The cross-sectional shape andarea of the cavity 323 is sized to allow the auto injector 140 to slideinto the cavity 323, but still hold the auto injector 140 securelywithout twisting or wobbling. A cap 322 is secured over the top end ofthe tube 327 to enclose and secure the auto injector 140 within thecavity 323. The cap 322 defines a hole 325 that is axially aligned withthe cavity 323 and sized to receive the drive rod 314.

As explained in more detail herein, the auto injector 140 has a housing102 and cover sleeve 103 that telescopes into the housing 102 (see,e.g., FIGS. 13-17). Sliding the cover sleeve 103 into the housing 102cocks the auto injector 140 so that the internal piston rod 107 is freeto move. To test the auto injector 140 in fixture 320, the prefilledsyringe 150 is removed from the auto injector 140 so that the piston rod107 is exposed. The auto injector 140 is then inserted in the cavity 323and orientated so that the cover sleeve 103 points upward and extendsfrom the top of the tube 327. The cap 322 is placed over the end of thetube 327. The drive rod 314 is then inserted through the hole 325 andinto the auto injector 140 so that the end of the drive rod 314 engagesthe end of the piston rod 107. A second, opposite end of the drive rod314 is coupled to testing equipment configured to move the drive rod 314at a substantially constant speed. The drive rod 314 also is attached tomeasuring equipment such as a load cell 315 (see, e.g., FIG. 5) that ispositioned to measure a force applied to the drive rod 314 as it moves.

The cap 322 is then pushed down until the cover sleeve 103 telescopesinto the housing 102, which cocks the auto injector 140 and frees theinjection spring 109 to decompress and the piston rod 107 to move. Thecap 322 is locked onto the end of the tube 327 so it stays in place. Anysuitable mechanism can be used to secure the cap 322 in place. Forexample, the cap 322 can be threaded onto the end of the tube 327.Alternatively, the tube 327 can include a key that projects form theside of the fixture 320 and the cap 322 can include an L-shaped slotthat receives the key and holds the cap 322 in place. The methods andtesting apparatuses disclosed herein also can be used to testalternative embodiments of spring-driven auto injectors.

At the start of the test, the injection spring 109 is compressed and thepiston rod 107 is in a position that corresponds to the stopper 157being in its first position. The drive rod 314 is then raised at aconstant speed and for a determined distance. In at least some possibleembodiments, the determined distance corresponds to the stopper 157moving from the first position, D1, to the second position, D2, todeliver a full dose of therapeutic fluid 160. For example, the drive rod314 can be raised about 30 mm. Additionally, the speed at which thedrive rod 314 is raised is selected to simulate a desired timing forinjection of the prefilled syringe 150 within an auto injector 140. Asthe drive rod 314 is raised and the piston rod 107 advances, the loadcell 315 measures the force applied to the drive rod 314 and therelative position of the drive rod 314. The displacement of the driverod 314 will substantially equal the displacement of the syringe stopper157. The force measurements and the displacement of the drive rod 314 atthe time of each force measurement are recorded to form a dispensingforce profile. Such force measurements can be used to verify theinjection spring 109 causes the piston rod 107 to exert a desireddispensing force as it advances between positions corresponding to thefirst and second positions D1, D2 of the stopper 157.

Although the fixture 320 is illustrated as holding an auto injector 140having a telescoping sleeve 103 to cock the auto injector 140 and freethe piston rod 107 to move, it can be adapted to hold and cock autoinjectors 140 having alternative mechanisms such as push buttons, knobs,levers, and sliding buttons.

FIG. 5 illustrates the fixture 315 shown in FIG. 4A in a test setup foroperating the drive rod 314 and measuring performance of the prefilledsyringe 150. In this set up, a universal testing machine 310 has a crosshead 312 that moves up and down and can be moved a constant anddetermined speed. The fixture 316 is mounted in the universal testingmachine 310 and positioned so that the drive rod 314 is axially alignedwith cross head 312. A load cell 315 is positioned between the drive rod314 and the cross head 312 and measures the force exerted against thedrive rod 314 as the cross head 312 moves downward or otherwise advancestoward the stopper 157. Additionally, a gauge for measuring displacementof the cross head 312 or drive rod 314 is positioned and configured tomeasure movement of the cross head 312. As noted herein, linear movementof the cross head 312 and drive rod 314 will be substantially equal tolinear movement of the syringe stopper 157. Although the fixture 316 isillustrated being used with the universal testing machine 310, it shouldbe appreciated that the fixture 319 illustrated in FIG. 4B and thefixture 320 illustrated in FIG. 4C can be used with the universaltesting machine 310 and drive rod 314 in a substantially similar manner.

The load cell 315, gauge, and universal testing machine 310 are operatedby a programmable controller 311 such as a computer that controlsmovement of the cross head 312 and records output from the load cell 315an instrument for measuring distance. Measurements from the load cell315 and the gauge are synchronized so that the recorded exertion forceis correlated to the displacement of the drive rod 314/stopper 157 atthe time a force measurement is made. The force and displacementmeasurements form an exertion force profile correlating the measuredforce to displacement of the drive rod 314 and stopper 157. This datacan be used to generate graphs and charts similar to those illustratedin FIGS. 3A-3C. The computer controller 311 also can record the timeintervals for each measurement made and the total time it takes to fullydisplace the stopper 157 for delivery of a full dose of therapeuticfluid 160.

The load cell 315 can be any type of instrument or sensor that measuresforce such as a strain gauge or piezo electric cell. The gauge can beany type of instrument for measuring distance including light-, laser-,and magnetic-based measuring instruments. The gauge also could bevirtual in that the motor driving the cross head 312 is a stepper motorand distance is determined by the number of steps during rotation of thearmature on the motor. An example of a universal testing machine 310that can be used is a MultiTest 2.5-I tensometer available from Mecmesinof the United Kingdom. An example of a load cell 315 may be of 25N or200N. An example of control software may be Emperor v1.18. Otheruniversal machines that can be adapted to measure force and displacementcan be used. In operation, and as discussed herein, the programmablecontroller 311 controls the universal testing machine 310 to move thecross head 312 at a substantially constant speed. Alternativeembodiments can apply acceleration or deceleration to movement of thecross head 312. In an alternative test setup, the fixture 320 holdingboth the prefilled syringe 150 and auto injector 140 can be used withthe universal testing machine 310.

It is desirable to select an injection spring 109 for an auto injector140 that has enough force to apply a dispensing force against thestopper 157 and to also operate the related subassemblies in the autoinjector 140 within a determined time, such as about 19 seconds, whenthe prefilled syringe 150 is subjected to accelerated aging so that thespring 109 specifications can be used in the regulatory approvalprocess. It is also desirable to select a spring 109 that is not toostrong and deliver the therapeutic fluid 160 too fast for acommercialized auto injector 140 and prefilled syringe 150 combination,especially because the effects of natural aging are not as significantas they are for artificial aging. The dispensing force is that portionof the spring force that is applied to the stopper 157 during operationof the auto injector 140, the remaining portion of the spring forceoperates any subassembly that is also driven by the injection spring109.

FIGS. 6-11 illustrate various methods to determine an injection spring109 having enough stored energy to: (i) move the syringe stopper 157 adesired distance along the path of travel, P, within a determined time;(ii) have enough stored energy to maintain a relatively steady speedmovement as the stopper 157 approaches the second position, D2, toprevent the stopper 157 from stalling; and (iii) operate components inthe auto injector 140 other than the piston rod 107 that also arepowered by the injection spring 109. Examples of components in the autoinjector 140 that are powered by the injection spring 109 include thepiston rod 107, the holding pin 106, and the holding sleeve 108, whichthe spring 109 holds distally against the bias of the cover sleevespring 110. In yet other alternative embodiments, the only structuremoved by decompression of the injection spring 109 is the syringestopper 157 itself. The portion of the syringe force that is applied tothe stopper 157 through the piston rod 107 is a dispensing force. Theremaining portion of the spring force that is used to operate mechanismsin the auto injector 140 other than the piston rod 107 is an operationforce.

FIG. 6 is a flowchart illustrating a determination process 200 by whichparameters can be selected for the injection spring 109 of an autoinjector 140. Examples of parameters for the injection spring 109include the spring constant, uncompressed spring length, and compressedspring length. The determination process 200 includes an age operation202, a test operation 204, and a select operation 206. The determinationprocess 200 optionally may include a second select operation 208.

At the age operation 202, one or more prefilled syringes 150, such asthe prefilled syringes 150 shown in FIG. 1, can be aged to at least asimulated age that is at least equal to the desired shelf life for thetherapeutic fluid 160 and the prefilled syringe 150. As shown in FIG. 7,in certain implementations, the prefilled syringes 150 or therapeuticfluid 160 are artificially aged using a heat source. For example, one ormore syringes 150 prefilled with a therapeutic fluid 160 can be disposedwithin an interior 182 of an oven 180. In some implementations, humidityis not controlled during the artificial aging process. In otherimplementations, humidity is controlled during the artificial agingprocess.

To accelerate aging for the prefilled syringe 150, one or more prefilledsyringes 150 are in an oven 180 at a predetermined temperature. Thegreater the temperature the faster the prefilled syringes 150 age to asimulated age. In some embodiments, the prefilled syringes 150 areheated at a temperature in the range from about 20° C. to about 60° C.For example, the prefilled syringes 150 can be heated at temperatures ofabout 5° C., about 25° C., or about 40° C. Each of the sample sets 170is kept at the predetermined temperature for a different period of time(e.g., minutes, days, weeks, months, years). The temperature and lengthof time for heating the prefilled syringes 150 can be determinedaccording to the Arrhenius calculation of Equation (1). The number ofprefilled syringes 150 that are heated to accelerate aging depends onthe number of samples to be tested for selection of an injection spring109. The more samples that are tested, the more data will be availableto select a spring 109. Additionally, sets of prefilled syringes 150 canbe heated at different temperatures or tested for different lengths oftime. Heating different sets of prefilled syringes 150 in this mannerallows data simulating different shelf lives and different circumstancesto be used in the spring 109 selection process.

At the test operation 204, one or more force tests can be performed onthe aged prefilled syringes 150 using any suitable testing techniquesincluding the testing techniques illustrated herein in more detail (see,e.g., FIGS. 4A, 4B, and 5). In general, the test or tests includemeasuring one or more exertion forces Fe applied to the stopper 157 ofeach prefilled syringe 150 as it moves from the first position, D1, tothe second position, D2, and as therapeutic fluid 160 is dispensed. Theexertion force measurements are associated with the correspondingposition (i.e., displacement) of the stopper 157 along the path oftravel P.

In some embodiments, the exertion force is measured for moving only thestopper 157 of the prefilled syringe 150 (see, e.g., FIGS. 4A and 5). Inother examples, the exertion force is measured for moving the stopper157 via the piston rod simultaneously operating other components of theauto injector that are powered by the injection spring (see, e.g., FIGS.4B and 5).

At the select operation 206, the measured exertion forces are analyzedto determine an injection spring 109 that has enough energy to deliver asuitable amount of force and that also has suitable parameters foroperating within the auto injector. The spring force is determinedaccording to Hooke's law:

F _(spring) =K(l ₀ −x)  (4)

where F_(spring) is the force of the spring, “K” is the spring constantfor the particular injection spring, l₀ is the uncompressed springlength, and x is the current spring length.

In the following, the term compression of the spring or springcompression in a determined state is used to refer to the differencebetween the uncompressed length of the spring and the length of thespring in said determined state. In least some embodiment such as autoinjector 140, there is a gap between the piston rod 107 and the stopper157 at the start of operation. At the start of operation, the injectionspring 109 must decompress slightly to engage the piston rod 107 againstthe stopper 157. In these embodiments, the spring length, at the startof operation—before actuation of the auto injector 140—is shorter thanan initial spring length, l_(i), when the piston rod 107 is against thestopper 157 and begins to push the stopper 157 from its first position,D1. In these embodiments, the dispensing force also can be modeled as:

F _(d) =K(C _(i) −x _(stopper)), wherein C _(i) =l ₀ −l _(i)  (5)

where C_(i) is the initial compression of the spring, l_(i) is thelength of the spring when the piston rod engages the stopper and thestopper is in the initial position, and x_(stopper) is the displacementof the stopper with reference to the first initial position of thestopper. In addition, the stored energy available for dispensing thedrug in the auto injector may be modeled as:

$\begin{matrix}{E = {\frac{1}{2}KC_{i}^{2}}} & (6)\end{matrix}$

Using these equations, a spring constant and uncompressed spring lengthfor the injection spring 109 can be selected to provide a sufficientdispensing force to the stopper 157 to successfully move the stopper 157along the path of travel, P for a displacement that is at least longenough to deliver a full dose of the therapeutic fluid 160 and within adesired time. It is noted that the initial spring length depends on thegeometry of the auto injector 140 such as the spring length at the startof operation (i.e., the assembled spring length or cocked length) andthe gap between the plunger rod 107 and the stopper 157 in the initialposition.

Because equations (4) and (5) are linear, a spring force for theinjection spring 109 can be represented in the graph shown in FIG. 3C bya line plotting a decreasing force over increasing displacement. In apossible embodiment, a measured exertion force may be used to determinethe suitable spring 109. In this embodiment, the reference force,F_(ref), used to calculate the spring force can be the maximum exertionforce measured as the drive rod 314 of the test equipment 310 moves thestopper 157 from the first position, D1, to the second position, D2. Foraccelerated aged prefilled syringes 150 as disclosed herein, thatmaximum exertion force can be a glide force measured as the stopper 157approaches the second position, D2, as illustrated in FIG. 3C. In otherembodiments or circumstances, the maximum exertion force can be a glideforce as the stopper 157 moves along an intermediate portion of the pathof travel, P. In yet other embodiments or circumstances, the maximumexertion force can be the break-loose force as the stopper 157 beginsmovement from the first position, D1.

An additional condition that may be used for determining the springparameters (e.g., spring constant, compressed length, uncompressedlength) may be that the final spring force should be no less than 50% ofthe initial spring force, which is the spring force for the injectionspring 109 when the piston rod 107 first engages the stopper 157 at thefirst position, D1. In other embodiments, the final spring force shouldbe no less than 60%, 70%, 80%, or 90% of the initial spring force. Thesedesign specifications and parameters for the injection spring 109 maylead to several alternatives for a suitable spring 109. Other conditionssuch as market availability and price may then be considered whenselecting an injection spring 109. In some embodiments, selecting asuitable spring 109 may involve maximizing a utility function includingone or several of the conditions mentioned herein. In some embodiments,the injection spring 109 has a spring force when the stopper 157 is atthe first position, D1, and is engaged by the piston rod 107 in therange from about 20 N to about 40 N. In some embodiments, the injectionspring 109 has a spring force when the stopper 157 is at the firstposition, D1 and is engaged by the piston rod 107 in the range fromabout 20 N to about 30 N. Additionally, in some embodiments, theinjection spring 109 can have a spring force when the stopper 157 is atthe second position, D2, in the range from about 14 N to about 20 N.Additionally, in some embodiments, the injection spring 109 can have aspring force when the stopper 157 is at the second position, D2, in therange from about 15 N to about 18 N.

In some embodiments, several measured exertion forces may be used todetermine the suitable spring 109. For example, an initial exertionforce (break loose force) may be used to determine the suitable spring109 together with exertion force(s) at the end of travel path, P. Inanother example, a reference energy for moving the stopper 157 in aprefilled syringe 150 may be calculated based on a measured forceprofile acquired by moving a stopper 157 using equipment as described inFIGS. 4-5. The reference energy may be calculated for a stopper 157moving in one or more aged reference prefilled syringes 150 or one ormore unaged prefilled syringes 150. In at least some embodiments, theselected spring 109 will have a stored energy when the stopper 157 is atthe first position, D1 and engaged by the piston rod 107 that is about25% or more than the reference stored energy. In other possibleembodiments, the stored energy is about 20%, 30%, 40%, 50%, or 60%greater than the reference stored energy. Therefore, a possible designparameter for some embodiments is that injection spring 109 has about25% more stored energy when the stopper 157 is at the first position,D1, and is engaged by the piston rod 107 than is actually required tomove the stopper 157 in an unaged prefilled syringe 150 from the firstposition, D1, to the second position, D2, without stalling. In someembodiments, the stored energy in the injection spring 109 when thestopper 157 is in the first position, D1, and is engaged by the pistonrod 107 is in the range from about 0.9 J to about 2 J.

Furthermore, it has been found that to ensure proper stopper 157movement, it is beneficial that the dispensing force when the stopper157 reaches the second position, D2, be as high as possible. Having thishigh dispensing force at the second position, D2, lowers the risk ofstalling at the end of the dose delivery. Further, it has been foundthat it is beneficial that the initial dispensing force be as low aspossible to avoid high initial impact. As a result, some possibleembodiments have injection springs 109 that have a longer initial springcompression length over an injection spring 109 having a high springconstant. In some embodiments, the spring parameters may be selected tomaximize the initial spring compression length of the injection spring109 and minimize the spring constant. In other words, when severalspring parameters would provide a suitable spring 109, the spring 109having the lowest spring constant and the highest initial compression ispreferred.

In some embodiments, the initial spring compression length is in therange from about 50 mm to about 100 mm with a spring constant in therange from about 0.2 N/mm to about 0.4 N/mm. In alternative embodiments,the initial spring compression length is in the range from about 75 mmto about 95 mm with a spring constant in the range from about 0.28 N/mmto about 0.32 N/mm. In another example, the spring constant is about 0.3N/mm.

Once the spring parameters are determined, an injection spring 109 isselected that will cause the piston rod 107 of the auto injector 140 toexert a dispensing force against the syringe stopper 157 that is greaterthan the maximum measured exertion force so that the injection spring109 will overcome all resistive forces acting against movement of thestopper 157 and have enough force to move the stopper 157 to the secondposition, D2, within a determined time.

Additionally, in some embodiments, parameters for the injection spring109 are selected based on a maximum exertion force measured duringtesting of prefilled syringes 150 exposed to accelerated aging. In otherexamples, the parameters for the injection spring 109 are selected basedon multiple exertion forces measured during the testing. For example,spring constants, uncompressed spring lengths, and compressed springlengths can be calculated based on or for the multiple exertion forces,which can provide a more favorable slope of the spring force as thespring 109 decompresses.

Additionally, the embodiment shown herein used a helical spring for theinjection spring 109. A helical spring is a linear rate spring. Otherembodiments can use other types of springs 109 such as conical springs,constant force springs, variable force springs, torsion springs, gassprings, or hydraulic springs. Hooke's law for springs such as gas andhydraulic springs is not linear. However, it is substantially linearover the first part of the gas or hydraulic spring's displacement andthe spring forces can still be approximated using equation (4) or asimilar linear relationship. In alternative embodiments, suitablemathematical relationships and models other than Hooke's law can be usedto determine forces for springs including linear and non-linear springs.

FIGS. 8-10 illustrate various testing processes 220, 230, 240 that areeach suitable for implementing the test operation 204 of thedetermination process 200. In certain implementations, the testingprocesses 220, 230, 240 are implemented using automated orsemi-automated testing equipment, such as the testing equipment 310described herein with relation to FIGS. 4A, 4B, and 5. Suitableprocesses for using the testing equipment 310 will be described in moredetail herein with reference to FIG. 11.

Each of the testing processes 220, 230, 240 can be performed on aprefilled syringe 150, either alone or in combination with an autoinjector 140 or components thereof. In some examples, the testingequipment 310 directly acts on the stopper 157 of a prefilled syringe150. In other examples, the testing equipment 310 acts on a drive member314 (e.g., piston rod 107) of the auto injector 140, which isoperationally coupled to the syringe stopper 157.

The prefilled syringe 150 may be naturally aged or artificially aged.Each of the testing processes 220, 230, 240 also can be performed onunaged prefilled syringes 150. In some examples, the testing processes220, 230, 240 are performed on prefilled syringes 150 prefilled with atherapeutic fluid 160. In other examples, the testing processes 220,230, 240 are performed on syringes 150 prefilled with other types offluid (e.g., saline or water).

FIG. 8 is a flowchart illustrating a first testing process 220 suitablefor implementing the test operation 204 of the determination process200. The first testing process 220 includes a move operation 222, ameasure operation 224, and a determine operation 226.

At the move operation 222, the stopper 157 of a prefilled syringe 150 ismoved distally within the syringe barrel 151 along the path of travel,P, at a constant speed. For example, the stopper 157 may be moved alongthe path of travel, P, from a first position (e.g., a proximal position,an initial position) D1 to a second position (e.g., a distal position, abottomed-out position) D2.

In certain implementations, the constant speed is selected to match adisplacement speed of the stopper 157 during an actual injection usingthe auto injector 140 in which the stopper 157 is moved from a firstposition, D1, to a second position, D2, and a full dose of fluid 160 isheld in the syringe barrel 151 between the first and second positionsD1, D2. For example, the constant speed may be selected to simulate adesired injection time in the range from about 5 seconds to about 19seconds. Another embodiment may select a constant speed to simulate aninjection time in the range from about 5 seconds to about 12 seconds.Another embodiment may select a constant speed to simulate an injectiontime in the range from about 6 seconds to about 20 seconds. Anotherembodiment may select a constant speed to simulate an injection time inthe range from about 8 seconds to about 15 seconds. Another embodimentmay select a constant speed to simulate an injection time in the rangefrom about 15 seconds to about 25 seconds. In certain examples, theconstant speed may be selected to simulate an injection time in therange from about 17 seconds to about 22 seconds. In an example, theconstant speed may be selected to simulate an injection time of about 12seconds. In an example, the constant speed may be selected to simulatean injection time of about 8 seconds. In an example, the constant speedmay be selected to simulate an injection time of about 18 seconds. In anexample, the constant speed may be selected to simulate an injectiontime of about 19 seconds. In an example, the constant speed may beselected to simulate an injection time of about 20 seconds. In certainexamples, the constant speed is selected to be in the range from about60 mm/min to about 360 mm/min. In other embodiments, the constant speedis selected to be between about 150 mm/min and about 200 mm/min. Incertain examples, the constant speed may be selected to be between about80 mm/min and about 90 mm/min. In an example, the constant speed isselected to be about 150 mm/min. In an example, the constant speed isselected to be about 86 mm/min. In an example, the constant speed isselected to be about 175 mm/min.

The measure operation 224 measures one or more exertion forces appliedto the stopper 157 to move the stopper 157 distally along the path oftravel, P, at the constant speed. In certain embodiments, the exertionforce utilized to initiate movement of the stopper 157 relative to thesyringe barrel 151 (i.e., the break-loose force) is measured. In otherembodiments, the exertion force utilized to maintain movement of thestopper 157 along the path of travel, P, within the syringe barrel 151(i.e., the glide force) is measured. For example, a maximum exertionforce applied during movement of the stopper 157 along the path oftravel, P, (i.e., a maximum glide force) may be measured. In certainexamples, the displacement of the stopper 157 is measured at the sametime as the exertion force is measured.

At the determine operation 226, a reference force for use in calculatinga suitable spring 109 is determined. In certain embodiments of theselect operation 206, the reference force is used to select a springconstant, uncompressed spring length, or compressed spring length.

In some implementations, the reference force is the maximum or peakforce the injection spring 109 needs to overcome to move the stopper 157along the path of travel, P, between the first and second positions D1,D2. Accordingly, the reference force is no less than the measuredexertion force being applied to the stopper 157 to overcome anyresistive forces that oppose the distal movement of the stopper 157along the path of travel, P. In certain embodiments, the reference forceis equal to the maximum measured exertion force and can be used todetermine parameters for the injection spring 109. In other embodiments,the reference force can be greater than the maximum measured exertionforce. In yet other embodiments, the reference force can be lower thanthe maximum measured exertion force. For example, the maximum measuredexertion force could be measured at a displacement outside the range ofthe first and second positions D1, D2 for the stopper 157.

In other implementations, the reference force is also determined basedon resistance forces generated by components of the auto injector 140.For example, the reference force also may account for one or morefriction forces generated by movement between two or more components(e.g., the piston rod 107, the support member 105, the indicator sleeve111, and the holding sleeve 108 shown in FIGS. 13-17) of the autoinjector 140. In an example, the reference force also may include theforce needed to move or operate one or more components (e.g., theholding pin 106, the holding sleeve 108) of the auto injector 140against the bias of another spring 109 (e.g., cover sleeve spring 110 ofFIGS. 13-17). The resistive forces generated by the auto injector 140may be separately measured, calculated or otherwise estimated.

FIG. 9 is a flowchart illustrating a second possible testing process 230suitable for implementing the test operation 204 of the determinationprocess 200. The second testing process 230 includes a move operation232, a measure operation 234, and a determine operation 236. The moveoperation 232 of the second testing process 230 is the same orsubstantially the same as the move operation 222 of the first testingprocess 220.

The measure operation 234 is substantially the same as the measureoperation 224 of the first testing process 220, except that multipleexertion force measurements are taken along the path of travel, P. Eachexertion force measurement is associated with the correspondingdisplacement of the stopper 157 along the path of travel, P. In someimplementations, two exertion force measurements are taken along thepath of travel, P, (e.g., at the first positon D1 and the secondposition D2). In other implementations, three or more exertion forcemeasurements are taken along the path of travel, P. In certain examples,the exertion force is measured at constant intervals along the path oftravel, P. In certain examples, the exertion force is continuouslymeasured along the path of travel, P.

In certain embodiments, the displacement of the drive rod 314, whichcorresponds to displacement of the plunger 157 also is measured. Thedisplacement can be measured at the same time as each measurement ismade of the exertion forces. In certain embodiments, the displacementand exertion force measurements can be correlated to form a forceprofile.

The determine operation 236 is the same or substantially the same as thedetermine operation 226 of the first testing process 220, except thattwo or more reference forces are determined. For example, one determinedreference force can correspond to the break-loose force, and anotherdetermined reference force can correspond to the maximum measured glideforce. In other embodiments, two or more determined reference forces cancorrespond to different measured glide forces. In other embodiments, onedetermined reference force can correspond to a glide or break-looseforce, and another determined reference can correspond to a displacementof the piston rod 107 for the auto injector 140 that is outside therange of displacement for the stopper 157. For example, a determinedreference force can correspond to the force needed to begin movement ofthe piston rod 107 before it engages the stopper 157.

In some embodiments, at least one reference force is determined based onan exertion force measured for pushing the stopper 157 from the first tothe second positions D1, D2 in the syringe barrel 151, and at leastanother reference force is determined based on the measured force orfriction related to moving or operating internal components of the autoinjector 140. And in yet another possible embodiment, at least onereference force is determined that corresponds to the exertion forcemeasured for operating internal components of the auto injector 140 andpushing the stopper 157.

FIG. 10 is a flowchart illustrating a third testing process 240 suitablefor implementing the test operation 204 of the determination process200. The third testing process 240 determines spring parameters suchthat an injection spring 109 having the determined spring parameters cansuccessfully drive the stopper 157 along the path of travel, P. Thethird testing process 240 includes a move operation 242, a measureoperation 244, a determine operation 246, a calculate operation 248, anda select operation 250.

The move operation 242 of the third testing process 240 is the same orsubstantially the same as the move operation 222 of the first testingprocess 220.

In some implementations, the measure operation 244 is the same orsubstantially the same as the measure operation 224 of the first testingprocess 220. In other implementations, the measure operation 244 is thesame or substantially the same as the measure operation 234 of thesecond testing process 230.

In some implementations, the determine operation 246 is the same orsubstantially the same as the determine operation 226 of the firsttesting process 220. In other implementations, the determine operation246 is the same or substantially the same as the determine operation 236of the second testing process 230.

The calculate operation 248 determines a corresponding spring constant,uncompressed spring length, or compressed spring length for each of theone or more reference forces determined in the determine operation 246.These spring parameters are calculated based on the determined referenceforce (which equals or otherwise corresponds to a measured exertionforce) and the corresponding displacement of the stopper 157. Thecalculated spring parameters are “reference spring parameters.”

In some embodiments, assuming an uncompressed spring length and an autoinjector geometry, the calculate operation 248 determines a minimumspring constant needed to generate an exertion force at a correspondingdisplacement position of the stopper 157 sufficient to drive the stopper157 along the path of travel, P. In other embodiments, the calculateoperation 248 determines a minimum spring constant needed to generatethe required exertion force and to overcome resistance forces generatedby the auto injector 140. In some embodiments, the uncompressed springlength also is determined by the calculate operation 248. In someembodiments, the calculate operation 248 determines the minimum springconstant and the maximum uncompressed spring length. In otherembodiments, the calculate operation 248 may determine the maximumspring constant.

The second determine operation 250 compares the reference springparameters determined in the calculate operation 248 to determineoptimal spring parameters. The optimal spring parameters can be chosenbased on a variety of different criteria such as desired injection time,desired spring forces, spring cost, and geometry of the auto injector140.

FIG. 11 is a flowchart 260 illustrating a method for performing at leastthe move operations 222, 232, 242 and the measure operations 224, 234,244 of the testing processes 220, 230, 240 using the testing equipment310 of FIGS. 4A, 4B, and 5. In certain implementations, the testingequipment 310 includes a tensometer or other mechanism for measuring anexertion force on the syringe stopper 157. As described above, thetesting equipment 310 may include a frame 316 to hold the prefilledsyringe 150.

In some examples, the operations of flowchart 260, and the otherflowcharts and operations discussed herein, are performed on a singleprefilled syringe 150. In other examples, however, the operations of theflowchart 260 are performed on multiple prefilled syringes 150. Incertain examples, the operations can be performed on prefilled syringes150 of various ages (e.g., natural ages or artificial ages). In certainexamples, the operations can be performed on unaged prefilled syringes150. In some examples, the operations of the flowchart 260 areimplemented using a prefilled syringe 150 by itself. In other examples,the operations can be implemented using a prefilled syringe 150 incombination with one or more parts of an auto injector 140.

In certain examples, portions of the auto injector 140 (e.g., portionsof the drive assembly) also can be mounted to the testing equipment 310as shown in FIG. 4B. In such examples, the frame 316 can be adapted tohold the auto injector 140 components. For example, an additional clamp317 can be mounted to the frame 316 to hold a drive member 314 (e.g.,piston rod 107) of the auto injector 140, the entire auto injector 140,or a portion thereof. In such examples, the drive rod 314 of the testingequipment 310 is operably coupled to the stopper 157 via the drivemember 314 of the auto injector 140.

At the actuate operation 266, the testing equipment 310 generates anexertion force on the syringe stopper 157. In certain examples, theactuate operation 266 includes advancing (e.g., lowering) the drive rod314 of the testing equipment 310 towards the stopper 157. In someexamples, the drive rod 314 is moved automatically. In other examples,the drive rod 314 is moved manually. In certain examples, the drive rod314 is moved at a constant speed.

In an example, the drive rod 314 is attached to a 25 N load cell. Inother embodiments, the drive rod 314 is attached to a 200 N load cell.Other load cells are possible that have a sufficient range ofsensitivity to measure the forces that can be applied to the drive rod314.

The measure operation 268 takes one or more measurements of the exertionforce being applied by the drive rod 314 to the stopper 157 as thestopper 157 moves along the path of travel, P. For example, the testingequipment 310 may automatically take measurements of the exertion forceapplied by the drive rod 314. The testing equipment 310 also tracks thedisplacement of the drive rod 314, which directly relates to thedisplacement of the syringe stopper 157. Accordingly, the measureoperation 268 results in one or more exertion force readings that areeach correlated with a determined displacement of the stopper 157.

In an example, an exertion force measurement may be taken when thestopper 157 initially moves relative to the syringe barrel 151. Inanother example, an exertion force measurement may be taken when thestopper 157 approaches or arrives at an end of the path of travel, P. Inanother example, multiple exertion force measurements may be taken atperiodic intervals or distances along the path of travel, P. In anotherexample, exertion force measurements are continuously taken along thepath of travel, P.

FIG. 12 is a flowchart illustrating an assembly process 280 forassembling an auto injector, such as an auto injector 140 of FIGS.13-17, with a prefilled syringe, such as prefilled syringe 150 of FIG.1, and the selected injection spring 109. The assembly process 280includes at least an obtain operation 284, a first install operation286, and a second install operation 288. The assembly process 280 mayoptionally include a select operation 282.

At the select operation 282, the user 190 selects a spring constant foran injection spring 109 to be installed in the auto injector 140 todrive injection of the prefilled syringe 150. The spring constant isselected to be sufficient to drive injection of the prefilled syringe150 even if the prefilled syringe 150 has artificially aged. The user190 can select the spring constant using any of the determinationprocesses 200 or testing processes 220, 230, 240 described herein.

At the obtain operation 284, the user 190 selects an injection spring109 having the selected spring parameters. The selected injection spring109 produces a biasing force at least sufficient to drive the syringestopper 157 within the syringe barrel 151 fully along the path oftravel, P. In certain examples, the selected injection spring 109produces a biasing force sufficient to drive the stopper 157 fully alongthe path of travel, P, and to perform other operations within the autoinjector 140. For example, the selected injection spring 109 issufficiently strong to bias the holding pin 106 and holding sleeve 108to a proximal position, to charge the cover sleeve spring 110, and todrive the stopper 157 along the path of travel, P.

In some implementations, the selected injection spring 109 is acompression spring. In some examples, the selected injection spring 109is a linear rate spring. In other examples, the selected injectionspring 109 is a variable rate spring. In still other examples, theselected injection spring 109 is a constant force spring. In otherimplementations, the selected injection spring 109 is a mechanical gasspring, a pneumatic spring, or a hydraulic spring.

At the first install operation 286, the selected injection spring 109 isinstalled in the auto injector 140. For example, the selected injectionspring 109 can be disposed within the outer body 102 of the autoinjector 140 as part of the drive assembly. In certain examples, theselected injection spring 109 is aligned with the piston rod 107 (e.g.,see FIG. 14). In an example, the selected injection spring 109 iscompressed between the piston rod 107 and the holding pin 106 (e.g., seeFIG. 14).

At the second install operation 288, the prefilled syringe 150 isinstalled in the auto injector 140. For example, a prefilled syringe 150can be mounted at the syringe holder 101 within the outer body 102.

FIGS. 13-17 illustrate an example auto injector 140 suitable forinjecting the prefilled syringe 150 of FIG. 1. FIG. 13 illustrates thecomponents of the auto injector 140 exploded from each other for ease inviewing. FIG. 14 is a cross-section of the auto injector 140 of FIG. 13,the auto injector 140 being disposed in a pre-injection configuration.FIG. 15 shows the auto injector 140 of FIG. 14 in a mid-injectionconfiguration. FIG. 16 shows the auto injector 140 of FIG. 14 in an endof injection configuration. FIG. 17 shows the auto injector 140 of FIG.16 rotated 90°. Although an example embodiment of an auto injector 140is disclosed and illustrated herein, any suitable spring-driven autoinjector can be used with the apparatuses and methods disclosed herein.

The auto injector 140 has a distal end 141 and a proximal end 142 (seeFIG. 14). The auto injector 140 is actuated by pushing the distal end141 against the body of a patient 180 at an injection site 198. The autoinjector 140 is held at the injection site 198 until a dosage oftherapeutic fluid 160 has been expelled from the prefilled syringe 150.

The auto injector 140 includes an outer housing 102 and an end cap 112mounted at the proximal end 142 of the outer housing 102. The autoinjector 140 also includes a syringe holder 101 disposed within theouter housing 102. The syringe holder 101 and the end cap 112 arestationary with respect to the housing 102. The syringe holder 101 isconfigured to hold a prefilled syringe, such as the prefilled syringe150 of FIG. 1.

A cover sleeve 103 is mounted at the distal end 141 of the outer housing102. The cover sleeve 103 is telescopically slidable relative to theouter housing 102 between an extended position (FIG. 14) and a retractedposition (FIG. 15). When in the extended position, the cover sleeve 103surrounds the syringe needle 155 of the prefilled syringe 150. Movingthe cover sleeve 103 to the retracted position exposes the syringeneedle 155.

A cover sleeve spring 110 extends between a first end 110 a and a secondend 110 b. The cover sleeve spring 110 extends over a first lengthbetween the first and second ends 110 a, 110 b when the cover sleeve 103is extended. The cover sleeve spring 110 is compressed to a secondlength between the first and second ends 110 a, 110 b when the coversleeve 103 is retracted. The second length is shorter than the firstlength. The cover sleeve spring 110 biases the cover sleeve 103 to theextended position. The cover sleeve 103 can be moved to the retractedposition against the bias of the spring 110, thereby compressing thespring 110. In the example shown, the spring 110 is a helical coilspring. In other examples, however, the spring 110 can be a gas-poweredspring, a pneumatic spring, a hydraulic spring, or any other type ofspring.

A needle cap remover 104 is initially disposed over the cover sleeve 103and engages the outer housing 102. The needle cap remover 104 inhibitsmovement of the cover sleeve 103 to the retracted position while theneedle cap remover 104 engages the cover sleeve 103 and outer housing102. The needle cap remover 104 grips a rigid needle shield that isinitially disposed about the needle 155 of the prefilled syringe 150.When removed from the auto injector 140, the needle cap remover 104entrains the rigid needle shield, thereby removing the rigid needleshield from the syringe needle 155.

A support member 105 is disposed within the outer housing 102 proximalof the syringe holder 101. The support member 105 is axially androtationally fixed to the end cap 112. The distal end of the supportmember 105 abuts against a proximal end of the syringe holder 101.

A drive assembly is disposed within the outer housing 102 proximal ofthe syringe holder 101. The drive assembly includes an injection spring109 and a subassembly biased by the injection spring 109. In the exampleshown, the injection spring 109 is a helical coil spring having avariable force. In other examples, however, the injection spring 109 canbe a conical spring, a torsion spring, a gas-powered spring, a pneumaticspring, a hydraulic spring, or any other type of variable force orconstant force spring. The injection spring 109 also can be any otherinjection spring 109 or structure that biases the piston rod 107 towardthe distal end 141 of the auto injector 140.

The drive or subassembly includes at least a piston rod 107 aligned withthe stopper 157 of the prefilled syringe 150. The piston rod 107 isaxially movable within the outer body 102 along a travel distancebetween a cocked position and a bottomed-out position. When in thecocked position, the piston rod 107 is proximally spaced from theprefilled syringe stopper 157. When in the bottomed-out position, thepiston rod 107 presses the stopper 157 against the proximally facingshoulder 151 a within the interior 154 of the prefilled syringe 150.

Because the piston rod 107 is spaced from the stopper 157 when in thecocked position, the injection spring 109 will not apply a dispensingforce against the stopper 157 immediately upon release and expansion ofthe spring 109. The injection spring 109 will decompress slightly andadvance the piston rod 107 a short distance until the piston rod 107engages the stopper 157. Once the piston rod 107 engages the stopper157, the injection spring 109 will continue to decompress, but resistiveforces from the prefilled syringe 150 such as resistance andhydrodynamic force will act against movement of the stopper 157 andhence against decompression of the injection spring 109.

The injection spring 109 extends between a first end 109 a and a secondend 109 b. The injection spring 109 is compressed to a first cockedlength between the first and second ends 109 a, 109 b when the pistonrod 107 is disposed in the cocked position (see FIG. 14). The injectionspring 109 is extended to a second length between the first and secondends 109 a, 109 b when the piston rod 107 is disposed in thebottomed-out position (see FIG. 16). The second length is longer thanthe first length.

The injection spring 109 applies an exertion force to bias the pistonrod 107 distally towards the bottomed-out position. In an example, theinjection spring 109 is disposed within a hollow interior of the pistonrod 107. For example, the first end 109 a of the injection spring 109may push against an inner shoulder of the piston rod 107 to bias thepiston rod 107 distally. The first length may be about 72 mm and thesecond length may be of about 106 mm. The injection spring 109 may havean uncompressed length of about 157 mm. A constant of the injectionspring 109 may be of about 0.30 N/mm.

In certain examples, the subassembly also includes a holding pin 106.The injection spring 109 biases the holding pin 106 proximally towardsthe end cap 112. For example, the second end 109 b of the injectionspring 109 may push against an inner shoulder of the holding pin 106. Incertain examples, the injection spring 109 is sandwiched between thepiston rod 107 and the holding pin 106. In an example, the injectionspring 109 biases the holding pin 106 proximally while biasing thepiston rod 107 distally.

The holding pin 106 has a locking configuration and a releasingconfiguration. When in the locking configuration, the holding pin 106engages the piston rod 107 to hold the piston rod 107 in an axiallyfixed position relative to the holding pin 106 against the bias of theinjection spring 109. In certain examples, the holding pin 106 holds thepiston rod 107 in the cocked position against the bias of the injectionspring 109. When in the releasing configuration, the holding pin 106releases the piston rod 107 to enable relative movement between thepiston rod 107 and the holding pin 106.

In particular, the holding pin 106 of the drive assembly includes arms106 a extending from fixed ends 106 d to free ends 106 c. The fixed ends106 d are attached to a base portion 106 e. The free ends 106 c definestop members 106 b, which move radially when the arms 106 a are flexed.In certain examples, the base portion 106 e is sized to extend into thepiston rod 107. In certain examples, the base portion 106 e is sized toextend through at least a portion of the injection spring 109 so thatthe injection spring 109 coils around the base portion 106 e.

The piston rod 107 defines recesses 107 a in which the stop members 106b of the holding pin 106 can seat. Accordingly, the holding pin 106 isdisposed in the locking configuration when the arms 106 a are flexedradially inwardly so that the stop members 106 b engage the recesses 107a to retain the piston rod 107 in the cocked position. The holding pin106 transitions to the releasing configuration when the arms 106 a flexradially outwardly to move the stop members 106 b away from the recesses107 a.

A holding sleeve 108 surrounds a portion of the holding pin 106. Theholding sleeve 108 moves axially between a distal position and aproximal position. When in the distal position, the holding sleeve 108retains the holding pin 106 in the locking configuration (see FIG. 14).In particular, the holding sleeve 108 radially aligns with the arms 106a and has a sufficiently small inner cross-dimension to inhibit outwardradial flexing of the arms 106 a. Accordingly, the holding sleeve 108inhibits outward radial movement of the stop members 106 b of theholding pin 106 from the recesses 107 a of the piston rod 107. When inthe proximal position, the holding sleeve 108 is axially offset from thestop members 106 b, thereby allowing the holding pin 106 to transitionto the releasing configuration.

Prior to injection, the holding sleeve 108 is biased to the distalposition by the cover sleeve spring 110 extended to the second length.In certain examples, the cover sleeve spring 110 biases the cover sleeve103 through the holding sleeve 108. For example, the first end 110 a ofthe cover sleeve spring 110 abuts the holding sleeve 108, which abuts aproximal end of the cover sleeve 103. Movement of the cover sleeve 103to the retracted position pushes the holding sleeve 108 to the proximalposition and compresses the cover sleeve spring 110 to the secondlength.

In certain implementations, the holding sleeve 108 has a telescopicconfiguration. For example, the holding sleeve 108 may include an outerbody 108 a and an inner body 108 b (see FIG. 16). The inner body 108 bis disposed around the support member 105. The inner body 108 b isrotationally fixed to, but axially movable relative to the supportmember 105. The outer body 108 a is disposed around the inner body 108b. The first end 110 a of the cover sleeve spring 103 abuts the outerbody 108 a to bias the holding sleeve 108 distally.

The outer body 108 a and inner body 108 b are rotationally fixedtogether. The outer body 108 a and inner body 108 b snap-fit to eachother to move axially together as a unit from the distal position to theproximal position. For example, the inner body 108 b has a ramped toothand the outer body 108 a defines a slot sized to receive the rampedtooth. The ramped tooth extends through the slot to be entrained by theouter body 108 a in the proximal direction. The ramped tooth cams out ofthe slot as the outer body 108 a is moved distal of the inner body 108b.

An indicator sleeve 111 is disposed within the outer housing 102proximal of the syringe holder 101. As will be described in more detailherein, interaction between the indicator sleeve 111 and othercomponents within the outer housing 102 generates noise (e.g., clicks)that audibly indicate stages of the injection (e.g., start of injectionand end of injection).

The indicator sleeve 111 is axially movable relative to the outerhousing 102 between a proximal position and a distal position. Forexample, the indicator sleeve 111 has wings 111 b that slide in slots105 a defined in the support member 105 to limit axial movement betweenthe indicator sleeve 111 and support member 105. The indicator sleeve111 is biased to the proximal position by the cover sleeve spring 110.In an example, the second end 110 b of the cover sleeve spring 110 abutsa portion of the indicator sleeve 111. Accordingly, the cover sleevespring 110 is sandwiched between the holding sleeve 108 and theindicator sleeve 111. In an example, the cover sleeve spring 110 issandwiched between the outer body 108 a of the holding sleeve 108 andthe wings 111 b of the indicator sleeve 111.

The indicator sleeve 111 limits axial movement of the holding pin 106relative to the outer body 102. For example, the indicator sleeve 111defines grooves in which the stop members 106 b of the holding pin 106ride during axial movement of the holding pin 106 between the respectivedistal and proximal positions. Engagement between the stop members 106 band the grooves limits distal movement of the holding pin 106 relativeto the indicator sleeve 111, which limits the distal movement of theholding pin 106 relative to the support member 105, which is axiallyfixed relative to the outer body 102.

The indicator sleeve 111 selectively engages the piston rod 107. Forexample, the indicator sleeve 111 may have one or more arms 111 c withdetents 111 d at the free ends. The arms 111 c flex to move the detents111 d radially relative to the piston rod 107. The detents 111 d aresized to snap into corresponding slots 107 c defined in the piston rod107.

FIG. 14 illustrates the auto injector 140 in a pre-injectionconfiguration. The needle cap remover 104 and rigid needle shield havebeen removed. The syringe stopper 157 is disposed at the first position,D1, along the path of travel, P, within the prefilled syringe 150. Thepiston rod 107 is held at a location spaced proximally from the syringestopper 157 by the holding pin 106.

The holding pin 106 and piston rod 107 are positioned relative to eachother such that the stop members 106 b of the holding pin 106 radiallyalign with the recesses 107 a of the piston rod 107. The holding sleeve108 is disposed in the distal position at which the holding sleeve 108(e.g., the inner body 108 b of the holding sleeve 108) radially alignswith the stop members 106 b of the holding pin 106.

Accordingly, the holding sleeve 108 presses the stop members 106 b intothe recesses 107 a and inhibits radial movement of the stop members 106b out of the recesses 107 a.

The indicator sleeve 111 also is disposed in the distal position. Thedetents 111 d of the indicator sleeve 111 are disposed within the slots107 c of the piston rod 107. The holding sleeve 108 (e.g., the innerbody 108 b of the holding sleeve 108) radially aligns with the detents111 d. The inner cross-dimension of the inner body 108 b of the holdingsleeve 108 is sufficiently small to retain the detents 111 d within theslots 107 c when radially aligned with the detents 111 d.

As shown in FIG. 15, injection is initiated by proximal movement of thecover sleeve 103 relative to the housing 102 to the retracted position.A proximal end of the cover sleeve 103 abuts the holding sleeve 108(e.g., an outer body 108 a of the holding sleeve 108) and pushes theholding sleeve 108 to its proximal position. When in the proximalposition, the holding sleeve 108 is not radially aligned with the stopmembers 106 b of the holding pin 106. Accordingly, the bias of theinjection spring 109 acting on the piston rod 107 is sufficient to camthe stop members 106 b out of the recesses 107 a in the piston rod 107.

Accordingly, the piston rod 107 is free to move distally under the biasof the injection spring 109 towards the stopper 157 of the prefilledsyringe 150. While moving distally, the piston rod 107 engages thestopper 157 of the prefilled syringe 150 and pushes the stopper 157distally along the path of travel, P, within the syringe barrel 151.Distal movement of the stopper 157 pushes the fluid 160 through theneedle 155 at the distal end 152 of the prefilled syringe 150.

Releasing the stop members 106 b from the recesses 107 a of the pistonrod 107 also frees the holding pin 106 for movement relative to thepiston rod 107. In certain implementations, the injection spring 109biases the holding pin 106 proximally towards the end cap 112.

The stop members 106 b of the holding pin 106 engage the distal end ofthe inner body 108 b of the holding sleeve 108. The holding pin 106entrains the inner body 108 b of the holding sleeve 108 during thisproximal movement until the inner body 108 b abuts the support member105. The impact between the inner body 108 b of the holding sleeve 108and the support member 105 creates a noise (e.g., a first click) thatprovides an audible indication that injection has started.

The stop members 106 b inhibit movement of the inner body 108 b of theholding sleeve 108 back to the distal position (see FIG. 16). The stopmembers 106 b do not engage the outer body 108 a of the holding sleeve108. Accordingly, the outer body 108 a can move distally over the stopmembers 106 b (see FIG. 16).

When the piston rod 107 begins moving distally, the piston rod 107entrains the indicator sleeve 111 via the engagement between the detents111 d and the slots 107 c. Accordingly, the piston rod 107 moves theindicator sleeve 111 to the distal position against the bias of thecover sleeve spring 110. Engagement between the wings 111 b of theindicator sleeve 111 and the support member 105 prohibits further distalmovement of the indicator sleeve 111.

When the indicator sleeve 111 is disposed in the distal position, thedetents 111 d are axially offset from the holding sleeve 108 (see FIG.17), which is disposed in the proximal position. Accordingly, thedetents 111 d are free to cam out of the slots 107 c of the piston rod107, thereby allowing the piston rod 107 to continue being moveddistally by the injection spring 109. When moved radially outwardly, thedetents 111 d engage the distal end of the holding sleeve 108 (e.g., theinner body 108 a), thereby preventing proximal movement of the indicatorsleeve 111. The body of the piston rod 107 prevents radially inwarddeflection of the arms 111 c and detents 111 d during injection.

As shown in FIG. 16, the piston rod 107 moves the stopper 157 within thesyringe barrel 151 until the stopper 157 bottoms out within the syringebarrel 151 (e.g., at the proximally facing shoulder 151 a). Theinjection spring 109 continues to press the piston rod 107 against thestopper 157 when the stopper 157 is disposed in the bottomed-outposition.

After injection is complete, the auto injector 140 is moved away fromthe injection site 198. The cover sleeve 103 is biased distally over theneedle 155. In particular, the cover sleeve spring 110 biases the outerbody 108 a of the holding sleeve 108 distally. The stop members 106 b ofthe holding pin 106 prevent distal movement of the inner body 108 b ofthe holding sleeve 108. Accordingly, the outer body 108 a moves distallyrelative to the inner body 108 b until the inner body 108 b and outerbody 108 a axially lock relative to each other. For example, a detent onthe inner body 108 b may snap into a recess defined by the outer body108 a.

Distal movement of the outer body 108 a of the holding sleeve 108 pushesthe cover sleeve 103 to the extended position. The outer body 108 a islocked from proximal movement by the inner body 108 b. The outer body108 a abuts the cover sleeve 103 to prevent proximal movement of thecover sleeve 103 back to the retracted position. Accordingly, the coversleeve 103 is locked in the extended position covering the syringeneedle 155.

As shown in FIG. 17, notches 107 d defined at the proximal end of thepiston rod 107 align with the detents 111 d of the indicator sleeve 111when the piston rod 107 reaches the bottomed-out position. The notches107 d allow the detents 111 d to cam radially inwardly, therebydisengaging from the holding sleeve 108. Releasing the detents 111 dfrom the holding sleeve 108 frees the indicator sleeve 111 for movementback to the proximal position under the bias of the cover sleeve spring110. The cover sleeve spring 110 pushes the indicator sleeve 111proximally against the end cap 112, which creates another noise (e.g., asecond click) that provides an audible indication that injection hasended.

An example of an auto injector suitable for use with the apparatuses,methods, and uses disclosed herein include the YpsoMate® brand autoinjector available from Yypsomed AG of Burgdof, Switzerland. Furtherdetails pertaining to example auto injectors suitable for use inactuating a prefilled syringe can be found in U.S. Publication No.2016/0008541, the disclosure of which is hereby incorporated byreference in its entirety. The methods, apparatuses, and uses disclosedherein can be used with any type of auto injector that injectstherapeutic fluid from a prefilled syringe.

The auto injectors and prefilled syringes disclosed herein, includingthose prefilled with the therapeutic fluids disclosed herein, are foruse as a medicament to treat or prevent migraine headaches as well asother diseases, conditions, chronic illnesses and disabilities, andother therapeutic purposes. The prefilled syringes and auto injectorscan be sold as a single unit with the prefilled syringe already insertedinto the auto injector. Alternatively, the prefilled syringe and autoinjector can be sold as a kit wherein the prefilled syringe and autoinjector are either separate from one another but combined in the samepackaging or sold together but in separate packages such that theprefilled syringe is in one package or box and the auto injector is in adifferent package or box.

FIG. 18 is a flowchart illustrating a use process 290 for using the autoinjector 140 with prefilled syringe 150 and the selected injectionspring 109. The disclosed methods and apparatuses can be used as needed,periodically or on a continuous schedule. For example, they can be usedonce a day, once a week, once a month, on a schedule of no more thanonce every month, no more than once every two months, no more than onceevery three months, or no more than once every four months. FIG. 19illustrates the auto injector 140 being actuated by a user 190. The useprocess 290 includes at least an align operation 294, a press operation296, and a hold operation 298. The use process 290 may optionallyinclude an obtain operation 292.

At the obtain operation 292, the user 190 obtains an auto injector 140containing a prefilled syringe 150. The auto injector 140 includes aninjection spring 109 having a spring constant that is sufficient todrive injection of the prefilled syringe 150 even if the prefilledsyringe 150 has aged. The injection spring 109 also is sufficientlystrong to perform other operations within the auto injector 140 (e.g.,charging the cover sleeve spring 110) in addition to biasing the stopper157.

At the align operation 294, a distal end 141 of the auto injector 140 isaligned with the injection site 198 at the body 192 of a user 190.

At the press operation 296, the distal end 141 of the auto injector 140is pressed against the injection site 198 (see FIG. 19). For example,the user 190 may push the outer body 102 of the auto injector 140distally towards the injection site 198 as the cover sleeve 103 retractsinto the outer body 102 to expose the needle 155. As described herein,retraction of the cover sleeve 103 within the body 102 automaticallyactuates the drive assembly to trigger injection of the prefilledsyringe 150.

At the hold operation 298, the user 190 holds the auto injector 140 atthe injection site 198 with the cover sleeve 103 retracted into theouter body 102 until the end of the injection. In certain examples, theend of the injection is indicated by an audible noise (e.g., a click)generated by the auto injector 140.

The methods, apparatuses, and uses disclosed herein have many aspectsincluding the following.

One aspect is a method of adapting an auto injector configured toactuate a prefilled syringe, the auto injector having an injectionspring having a spring constant, the prefilled syringe being filled witha volume of therapeutic fluid, the prefilled syringe including a barrel,stopper, and a needle, the stopper having a path of travel, theinjection spring arranged to move the stopper along the path of travelthe method comprising: aging the prefilled syringe at an acceleratedrate to form an aged prefilled syringe; moving the stopper within thebarrel of the aged prefilled syringe at a predetermined speed from atleast a first position along the path of travel to at least a secondposition along the path of travel; measuring a plurality of exertionforces exerted on the stopper as the stopper moves within the barrelalong the path of travel; determining a resistive force opposingmovement of the stopper along the path of travel, the resistive forcecorresponding to the plurality of exertion forces; and selecting aspring constant for the injection spring, the act of selecting thespring constant comprising selecting the spring constant to correspondto the resistive force.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the operativeprefilled syringe includes an operative barrel and an operative stoppermovably positioned within the operative barrel, the operative stoppermovable along an operative path of travel from a first operativeposition to a second operative position, the auto injector to comprisean injection spring having a spring force, the injection springconfigured to apply a dispensing force to the operative stopper bydriving a piston rod toward the operative stopper upon actuation of theauto injector, the dispensing force being at least a portion of thespring force, the method comprising: aging a prefilled syringe at anaccelerated rate to form a reference prefilled syringe, the referenceprefilled syringe including a reference barrel and a reference stopperpositioned in the reference barrel; moving the reference stopper of thereference prefilled syringe along a reference path of travel from atleast a first reference position to at least a second referenceposition; as the reference stopper moves within the reference barrelalong the reference path of travel, measuring a plurality of exertionforces applied to the reference stopper and measuring a plurality ofreference stopper positions; generating an exertion force profile, theexertion force profile including at least some of the exertion forcesand reference stopper positions measured while the reference stopper wasmoving between the first and second reference positions, at least one ofthe measured exertion forces correlating to at least one of the measuredreference stopper positions; and selecting the injection spring so thatthe dispensing force applied to the operative stopper at each positionof the operative stopper as it moves along the operative path of travelbetween the first and second operative positions is greater than themeasured exertion force at a corresponding one of the measured referencestopper positions.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein selecting theinjection spring comprises selecting a measured exertion force from theexertion force profile, and selecting at least one spring parameter, theselected at least one spring parameter corresponding to the selectedexertion force.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein selecting theat least one spring parameter comprises selecting a spring constant forthe injection spring and an uncompressed length for the injectionspring.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein selecting atleast one spring parameter comprises selecting a spring constant and afirst compressed spring length corresponding to the reference stopperbeing at the first reference position along the reference path oftravel.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein selecting atleast one spring parameter comprises selecting a spring constant and asecond compressed spring length corresponding to the reference stopperbeing at a position along the reference path of travel corresponding toa maximum measured exertion force in the exertion force profile.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the selectedspring has a dispensing force when the stopper is at the second finalposition that is greater than about 50% of the dispensing force when thestopper is at the first initial position.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein thepredetermined speed corresponds to a speed required to move theoperative stopper along the operative path of travel from the firstoperative position to the second operative position in a range fromabout 5 seconds to about 19 seconds.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein: a plunger isoperably connected to the stopper and the act of moving the stoppercomprises moving the plunger; and the act of measuring a plurality ofexertion forces exerted on the stopper comprises measuring a pluralityof exertion forces exerted on the plunger.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the act ofdetermining the glide force includes determining the glide forcerequired to move the stopper along the path of travel from the firstposition to the second position within a determined amount of time.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein determiningthe first resistive force comprises determining the first resistiveforce when moving the stopper from the first position.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein determining aresistive force comprises determining a resistive force selected fromthe group of: a break loose force, a maximum glide force, orcombinations thereof.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein determining aresistive force comprises determining a resistive force selected fromthe group consisting of: a break loose force, a maximum glide force, orcombinations thereof.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein determining aresistive force comprises determining at least first and secondresistive forces, the first resistive force being a break loose force,and the second resistive force being a minimum glide force for movingthe stopper along the path of travel from the first position at abeginning of the path of travel to the second position at an end of thepath of travel without stalling.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein thedetermined amount of time is in the range from about 5 s to about 25 s.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the act ofdetermining the minimum glide force includes determining the minimumglide force required to move the stopper along the path of travel fromthe first position to the second position within about 5 seconds toabout 25 seconds.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the agedprefilled syringe holds a determined volume of therapeutic fluid betweenthe first position and the second position, and the act of determining aminimum glide force required to move the stopper along the path oftravel from the first position to the second position without stallingcomprises ejecting the determined volume of therapeutic fluid from theaged prefilled syringe.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein thedetermined volume is in the range from about 1.51 mL to about 1.66 mL.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the autoinjector comprises a subassembly, the subassembly movable in response todecompression of the injection spring, the subassembly arranged toselectively move the stopper, the act of selecting the spring constantcomprising: selecting the spring constant to correspond to at least thefirst resistive force, the second resistive force, and a third resistiveforce, the third resistive force resistive to movement of thesubassembly.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein moving thestopper within the barrel of the aged prefilled syringe comprises movingthe subassembly of the auto injector.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the autoinjector comprises a subassembly, the subassembly operable in responseto decompression of the injection spring, at least a portion of thesubassembly arranged to selectively move the stopper, the act ofselecting the spring constant comprising: selecting the spring constantto correspond to a force strong enough to operate the subassembly and tomove the stopper from the first position to the second position withoutstalling.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein moving thestopper within the barrel of the aged prefilled syringe comprises movingthe subassembly of the auto injector.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein thetherapeutic fluid comprises an antibody.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the antibodycomprises a humanized monoclonal antibody.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the humanizedmonoclonal antibody comprises an immunoglobulin G2 (IgG2) antibody.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the humanizedmonoclonal antibody comprises an anti-calcitonin gene-related peptideantibody.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein thetherapeutic fluid has a viscosity in the range from about 4 cSt to about14 cSt at 22° C.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein thetherapeutic fluid comprises fremanezumab and has a viscosity in therange from about 4 cSt to about 14 cSt at 22° C.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the barrel ofthe prefilled syringe comprises an inner surface, and the prefilledsyringe further comprises a lubricant on the inner surface.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the lubricantcomprises silicone oil.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the lubricantcomprises polydimethylsiloxane.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the siliconeoil coats the inner surface of the barrel and the thickness of thecoating is between about 0.1 μm and about 0.3 μm before the prefilledsyringe is aged.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the lubricantcomprises between about 0.35 mg and about 1.1 mg of silicone oil beforethe prefilled syringe is aged.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the siliconeoil has a viscosity between about 500 cSt and about 1500 cSt at 25° C.before the prefilled syringe is aged.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein aging theprefilled syringe comprises heating the prefilled syringe for adetermined period of time.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein thedetermined period of time is calculated according to the Arrheniusequation.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein: thedetermined period of time is calculated according to the Arrheniusequation; and heating the prefilled syringe for a determined period oftime comprises heating the prefilled syringe at a temperature in therange from about 20° C. to about 60° C.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the barrel ofthe prefilled syringe has a volume selected from the group of about 1 mLto about 2.25 mL.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the barrel ofthe prefilled syringe has a volume selected from the group consisting ofabout 1 mL to about 2.25 mL.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the distancebetween the first reference position of the reference stopper and thesecond reference position of the reference stopper is in the range fromabout 25.7 mm to about 30 mm.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the distancebetween the first position of the stopper and the second position of thestopper is in the range from about 35 mm to about 55 mm.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the needledefines a channel and the channel has a diameter in the range from about0.15 mm to about 0.3 mm.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the channeldefined by the needle has a length in the range from about 15 mm toabout 25 mm.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the barrelcomprises glass.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the barrelcomprises Borosilicate glass.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the barrel ofthe prefilled syringe has an inner diameter in the range from about 6 mmto about 10 mm.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the stoppercomprises ethylene tetrafluoroethylene.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring is a spring selected from the group of: a variable force spring,a constant force spring, a helical spring, a conical spring, a torsionspring, a gas spring, a hydraulic spring, and combinations thereof.

Another aspect is a method, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring is a spring selected from the group consisting of: a variableforce spring, a constant force spring, a helical spring, a conicalspring, a torsion spring, a gas spring, a hydraulic spring, andcombinations thereof.

Another aspect is an auto injector for actuating a prefilled syringecontaining a dosage of a therapeutic fluid, alone or in any combinationwith the previous embodiments and aspects disclosed herein, wherein thetherapeutic fluid comprising fremanezumab, and the auto injector made bya process comprising: any combination of the actions recited above;selecting a spring having the selected spring constant; and assemblingthe auto injector with the selected spring.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, the auto injectorarrangement comprising: a prefilled syringe including a barrel extendingalong a longitudinal axis between a distal end and a proximal end, aninner diameter of the barrel being about 8.65 mm, a needle disposed atthe distal end of the barrel, the needle having an inner diameter ofabout 0.21 mm and a length of about 20 mm or less, a therapeutic fluidheld within the barrel, a viscosity of the therapeutic fluid being inthe range of about 14 cSt or less at 22° C., and a stopper disposedwithin the barrel to retain the fluid within the barrel, the barreldefining a path of travel for the stopper, the path of travel having afirst position for the stopper and a second position for the stopper,the therapeutic fluid comprising fremanezumab; and an auto injectorholding the prefilled syringe, the auto injector comprising a plungerand an injection spring, the plunger engaging the stopper, and theinjection spring biasing the plunger towards the stopper, the injectionspring having a spring force of at least about 20 N when the stopper ispositioned at the first position.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, the auto injectorarrangement comprising: a prefilled syringe including a barrel extendingalong a longitudinal axis between a distal end and a proximal end, aninner diameter of the barrel being of about 8.65 mm, a needle disposedat the distal end of the barrel, the needle having an inner diameter ofabout 0.27 mm and a length of about 19.5 mm or less, a volume in therange from about 1.51 mL to about 1.66 mL of therapeutic fluid heldwithin the barrel, the therapeutic fluid comprising fremanezumab, aviscosity of the therapeutic fluid being about 8.8 cSt at 22° C., and astopper disposed within the barrel to retain the therapeutic fluidwithin the barrel, the barrel defining a path of travel for the stopper,the path of travel having a first initial position for the stopper and asecond final position for the stopper, the first position being aninitial position of the stopper before delivery of the therapeuticfluid, the second position being a final position of the stopper upondelivery of a full dose of the therapeutic fluid; and an auto injectorholding the prefilled syringe, the auto injector comprising an injectionspring arranged to apply a dispensing force to the stopper by driving apiston rod toward the stopper, wherein, when the auto injector isactuated, the injection spring is configured to provide an initialdispensing force to the stopper of at least about 20 N when the stopperis positioned at the first initial position and a final dispensing forceof about 12 N or greater to the stopper when the stopper is positionedat the second final position, the dispensing force being at least aportion of a spring force for the injection spring.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspect disclosed herein, wherein the injectionspring is configured to provide a final dispensing force of at least12.5 N to the stopper when the stopper is positioned at the second finalposition.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspect disclosed herein, wherein the injectionspring is configured to provide a final dispensing force of at least 14N to the stopper when the stopper is positioned at the second finalposition.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspect disclosed herein, wherein the injectionspring is configured to provide a final dispensing force of at least 12N to the stopper when the stopper is positioned at the second finalposition and the prefilled syringe has an accelerated age of about 24months.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring has a spring force in the range from about 20 N to about 30 Nwhen the stopper is positioned at the first initial position.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring is configured to provide a final dispensing force in the rangefrom about 12 N to about 20 N when the stopper is positioned at thesecond final position.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring is configured to provide a final dispensing force in the rangefrom about 12.5 N to about 20 N when the stopper is positioned at thesecond final position.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, when the stopper isat the first initial position, an actual stored spring energy of theinjection spring is at least about 25% greater than a minimum storedspring energy required to move the stopper from the first position tothe second position without stalling an unaged prefilled syringe.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring has a stored energy in the range from about 0.9 J to about 2 Jwhen the injection spring is in the first position.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring has a spring constant in the range from about 0.2 N/mm to about0.4 N/mm and a compressed length when in the first initial position inthe range from about 50 mm to about 100 mm.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring has a spring constant in the range from about 0.28 N/mm to about0.32 N/mm and compressed length when in the first initial position inthe range from about 75 mm to about 95 mm.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring has a force sufficient to move the stopper along the path oftravel from the first position to the second position within about 5seconds to about 25 seconds.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein: the barrelof the prefilled syringe comprises glass and defines an inner surface;and the prefilled syringe further comprises between about 0.4 mg andabout 1.1 mg of silicone oil on the inner surface before the prefilledsyringe is aged.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring is configured to move the stopper along the path of travel fromthe first position to the second position within the range from about 5seconds to about 19 seconds.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the siliconeoil has a viscosity between about 500 cSt and about 1500 cSt at 25° C.before the prefilled syringe is aged.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the siliconeoil has a viscosity of about 1000 cSt at 25° C. before the prefilledsyringe ages.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the stopperhas a length in the range from about 7.3 mm to about 8.1 mm.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the stopperhas a compressed state and an uncompressed state, and the stoppercomprises: a main body, the main body being substantially cylindricaland having a diameter in the uncompressed state in the range from about8.85 mm to about 9.05 mm; and at least one annular rib, the annular ribextending radially from the main body, the annular rib having an outerdiameter in the uncompressed state in the range from about 9.25 mm toabout 9.45 mm.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein a portion ofthe stopper is coated with ethylene tetrafluoroethylene, and a portionof the stopper is coated with silicone.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein a distancebetween the first position for the stopper and the second position forthe stopper is in the range from about 25.7 mm to about 30 mm.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the prefilledsyringe has a volume selected from the group of about 1 mL and about2.25 mL.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the prefilledsyringe has a volume selected from the group consisting of about 1 mLand about 2.25 mL.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein thetherapeutic fluid has a viscosity in the range from about 4 cSt to about10 cSt at 22° C.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, wherein the injectionspring is determined according to the actions recited in claim 1.

Another aspect is an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, the auto injectorarrangement comprising: a prefilled syringe; the prefilled syringecomprising a barrel formed at least in part by glass, a needle in fluidcommunication with the barrel, and a stopper positioned in the barrel,the barrel defining an inner surface, the barrel having an innerdiameter, the barrel being about 8.65 mm and a volume of about 2.25 mL,the barrel defining a path of travel for the stopper, the path of travelhaving a first position for the stopper and a second position for thestopper, the needle having an inner diameter of about 0.21 mm and alength of about 20 mm or less, a therapeutic fluid held within thebarrel, a viscosity of the therapeutic fluid being in the range of about10 cP or less at 22° C., the therapeutic fluid comprising fremanezumab;about 0.35 mg to about 1.1 mg of silicone oil lubricating the innersurface of the barrel, the silicone oil having a viscosity between about500 cSt and about 1500 cSt at 25° C. before the prefilled syringe isaged; and an auto injector holding the prefilled syringe, the autoinjector comprising a plunger and an injection spring, the plungerengaging the stopper, and the injection spring biasing the plungertowards the stopper, the injection spring when in the first position:has a force determined according to the actions recited in claim 1; isin the range from about 20 N to about 30 N; is about 25% greater thanspring force required to move the stopper from the first position to thesecond position without stalling before the prefilled syringe is aged;and has a force sufficient to move the stopper along the path of travelfrom the first position to the second position within about 5 seconds toabout 25 seconds.

Another aspect is an auto injector apparatus for actuating a prefilledsyringe containing a dosage of a therapeutic fluid, alone or in anycombination with the previous embodiments and aspects disclosed herein,the therapeutic fluid comprising an immunoglobulin G2 (IgG2) humanizedmonoclonal antibody, the auto injector made by a process comprising theoperations of: aging the prefilled syringe to form an aged prefilledsyringe; moving the stopper within the barrel of the aged prefilledsyringe at a predetermined speed from at least a first position alongthe path of travel to at least a second position along the path oftravel; measuring a plurality of exertion forces exerted on the stopperas the stopper moves within the barrel along the path of travel;determining at least first and second resistive forces opposing movementof the stopper along the path of travel, the first and second resistiveforces corresponding to the plurality of exertion forces; selecting aspring constant for the injection spring, the act of selecting thespring constant comprising selecting the spring constant to correspondto at least one of the first and second resistive forces; selecting aspring having the selected spring constant; and assembling the autoinjector with the selected spring.

Another aspect is an auto injector apparatus configured to move astopper within a barrel of a syringe to effect delivery of a fluid fromthe syringe, alone or in any combination with the previous embodimentsand aspects disclosed herein, the auto injector apparatus comprising: asyringe barrel, the syringe barrel having an empty state and a filledstate, the empty state occurring before the filled state, the syringeholding a dose of therapeutic fluid when in the filled state, thetherapeutic fluid comprising an immunoglobulin G₂ (IgG2) humanizedmonoclonal antibody; a stopper positioned in the syringe barrel, thestopper having a path of travel between a first position and a secondposition, the dose of therapeutic fluid being substantially positionedbetween the first and second positions; and an injection spring having aspring constant, the spring constant providing the injection spring witha first spring force that is at least 25% greater than a second springforce, the first spring force corresponding to the minimum spring forcerequired to move the stopper from the first position to the secondposition when the barrel is in the filled state, and the second springforce corresponding to the minimum spring force required to move thestopper from the first position to the second position when the barrelis in the empty state.

Another aspect is an auto injector apparatus configured to move astopper within a barrel of a syringe to effect delivery of a fluid fromthe syringe, alone or in any combination with the previous embodimentsand aspects disclosed herein, the auto injector apparatus comprising: aprefilled syringe, the prefilled syringe having an unaged state and anaged state, the prefilled syringe holding a dose of therapeutic fluidwhen in the filled state, the therapeutic fluid comprising animmunoglobulin G2 (IgG2) humanized monoclonal antibody; a stopperpositioned in the prefilled syringe, the stopper having a path of travelbetween a first position and a second position, the dose of therapeuticfluid being substantially positioned between the first and secondpositions; and an injection spring having a spring constant, the springconstant providing the injection spring with a first spring force thatis at least 25% greater than a second spring force, the first springforce corresponding to the minimum spring force required to move thestopper from the first position to the second position when theprefilled syringe is in the aged state, and the second spring forcecorresponding to the minimum spring force required to move the stopperfrom the first position to the second position when the prefilledsyringe is in the unaged state.

Another aspect is a prefilled syringe combination, alone or in anycombination with the previous embodiments and aspects disclosed herein,for use as a medicament to treat or prevent migraine headaches

Another aspect is a prefilled syringe containing fremanezumab, alone orin any combination with the previous embodiments and aspects disclosedherein, for use as a medicament to treat or prevent migraine headaches.

Another aspect is a prefilled syringe containing a therapeutic fluidcomprising fremanezumab, alone or in any combination with the previousembodiments and aspects disclosed herein, for use as a medicament totreat or prevent migraine headaches.

Another aspect is a prefilled syringe containing a therapeutic fluidcomprising fremanezumab and formulated at 150 mg/mL nominalconcentration in 16 mM histidine, 6.6% sucrose, 0.136 mg/mL EDTA, 1.2mg/mL P580, pH 5.5, alone or in any combination with the previousembodiments and aspects disclosed herein, for use as a medicament totreat or prevent migraine headaches.

Another aspect is a prefilled syringe containing fremanezumab in anycombination with an auto injector, alone or in any combination with theprevious embodiments and aspects disclosed herein, for use as amedicament to treat or prevent migraine headaches, the prefilled syringefilled with a therapeutic fluid formulated at 150 mg/mL nominalconcentration in 16 mM histidine, 6.6% sucrose, 0.136 mg/mL EDTA, 1.2mg/mL P580, pH 5.5.

Another aspect is a prefilled syringe containing fremanezumab for use asa medicament to treat or prevent migraine headaches, according to acontinuous schedule of no more than once every two months, either aloneor in any combination with the previous embodiments and aspects.

Another aspect is a prefilled syringe containing fremanezumab for use asa medicament to treat or prevent migraine headaches, according to acontinuous schedule of no more than once every three months, eitheralone or in any combination with the previous embodiments and aspects.

Another aspect is a prefilled syringe containing fremanezumab for use asa medicament to treat or prevent migraine headaches, according to acontinuous schedule of no more than once every four months, either aloneor in any combination with the previous embodiments and aspects.

Another aspect is an auto injector, either alone or in any combinationwith any of the previous embodiments and aspects, the auto injectorcomprising: a prefilled syringe comprising a stopper and a therapeuticfluid including fremanezumab; and an auto injector having an injectionspring and a piston rod arranged to move the stopper from a firstposition to a second position with a force of about 30 N or less and inabout 19 seconds or less, the distance between the first and secondpositions corresponding to one dose of the therapeutic fluid.

The various embodiments described above are provided by way ofillustration only and should not be construed to limit the claimsattached hereto. Those skilled in the art will readily recognize variousmodifications and changes that may be made without following the exampleembodiments and applications illustrated and described herein, andwithout departing from the true spirit and scope of the followingclaims. It is intended that any such modifications and equivalents beincluded in the scope of the claims.

1.-45. (canceled)
 46. A method of operating an auto injector apparatus,the method comprising: providing an auto injector holding a prefilledsyringe, the auto injector comprising an injection spring arranged toapply a dispensing force to the stopper by driving a piston rod towardthe stopper, the prefilled syringe including a barrel extending along alongitudinal axis between a distal end and a proximal end, an innerdiameter of the barrel being of about 8.65 mm, a needle disposed at thedistal end of the barrel, the barrel defining a path of travel for thestopper, the path of travel having a first initial position for thestopper and a second final position for the stopper, the first positionbeing an initial position of the stopper before delivery of thetherapeutic fluid, the second position being a final position of thestopper upon delivery of a full dose of the therapeutic fluid, theneedle having an inner diameter of about 0.27 mm and a length of about19.5 mm or less, the prefilled syringe initially holding a volume oftherapeutic fluid in the range from about 1.51 mL to about 1.66 mL oftherapeutic fluid held within the barrel, the therapeutic fluidcomprising fremanezumab, a viscosity of the therapeutic fluid beingabout 8.8 cSt at 22° C., and a stopper disposed within the barrel toretain the therapeutic fluid within the barrel; actuating the autoinjector; providing an initial dispensing force to the stopper of atleast about 20 N when the stopper is positioned at the first initialposition; and providing a final dispensing force of at least 12 N to thestopper when the stopper is positioned at the second final position, thedispensing force being at least a portion of a spring force for theinjection spring.
 47. The method of claim 46, wherein the act ofproviding a final dispensing force comprises providing a finaldispensing force of at least 12.5 N to the stopper when the stopper ispositioned at the second final position.
 48. The method of claim 47,wherein, wherein the act of providing a final dispensing force comprisesproviding a final dispensing force of at least 14 N to the stopper whenthe stopper is positioned at the second final position.
 49. The methodof claim 46, wherein the act of providing a final dispensing forcecomprises providing final dispensing force of at least 12 N to thestopper when the stopper is positioned at the second final position andthe prefilled syringe has an accelerated age of about 24 months.
 50. Themethod of claim 46, wherein the act of providing an initial dispensingforce comprises providing an initial dispensing force in a range fromabout 20 N to about 40 N when the stopper is positioned at the firstinitial position.
 51. The method of claim 47, wherein, wherein the actof providing a final dispensing force comprises providing a finaldispensing force in the range from about 12 N to about 20 N when thestopper is positioned at the second final position.
 52. The method ofclaim 46, wherein, when the stopper is at the first position, an actualstored spring energy of the injection spring is at least 25% greaterthan a minimum stored spring energy required to move the stopper fromthe first initial position to the second final position without stallingan unaged prefilled syringe.
 53. The method of claim 46, wherein theinjection spring has a stored energy in the range from about 0.9 J toabout 2 J when the injection spring is in the first initial position.54. The method of claim 53, wherein the injection spring has a springconstant in the range from about 0.2 N/mm to about 0.4 N/mm and acompressed length when in the first initial position in the range fromabout 50 mm to about 100 mm.
 55. The method of claim 54, wherein theinjection spring has a spring constant in the range from about 0.28 N/mmto about 0.32 N/mm and a compressed length when in the first initialposition in the range from about 75 mm to about 95 mm.
 56. The method ofclaim 55, further comprising moving the stopper along the path of travelfrom the first initial position to the second final position within therange from about 5 seconds to about 19 seconds.
 57. The method of claim46, wherein: the barrel of the prefilled syringe comprises glass anddefines an inner surface; and the prefilled syringe further comprisesbetween about 0.4 mg and about 1.1 mg of silicone oil on the innersurface before the prefilled syringe ages.
 58. The method of claim 57,wherein the silicone oil has a viscosity of about 1000 cSt at 25° C.before the prefilled syringe ages.
 59. The method of claim 46, whereinthe stopper has a length in the range from about 7.3 mm to about 8.1 mm.60. The method of claim 59, wherein the stopper has a compressed stateand an uncompressed state, and the stopper comprises: a main body, themain body being substantially cylindrical and having a diameter in theuncompressed state in the range from about 8.85 mm to about 9.05 mm; andat least one annular rib, the annular rib extending radially from themain body, the annular rib having an outer diameter in the uncompressedstate in the range from about 9.25 mm to about 9.45 mm.
 61. The methodof claim 59, wherein a portion of the stopper is coated with ethylenetetrafluoroethylene, and a portion of the stopper is coated withsilicone.
 62. The method of claim 46, further comprising moving thestopper along the path of travel from the first initial position to thesecond final position within the range from about 25.7 mm to about 30mm.
 63. A method of operating an auto injector apparatus, the methodcomprising: providing an auto injector holding a prefilled syringe, theauto injector comprising an injection spring arranged to apply adispensing force to the stopper by driving a piston rod toward thestopper, the prefilled syringe including a barrel extending along alongitudinal axis between a distal end and a proximal end, the barreldefining a path of travel for the stopper, the path of travel having afirst initial position for the stopper and a second final position forthe stopper, the first position being an initial position of the stopperbefore delivery of the therapeutic fluid, the second position being afinal position of the stopper upon delivery of a full dose of thetherapeutic fluid, the prefilled syringe initially holding a volume oftherapeutic fluid in the range from about 1.51 mL to about 1.66 mL oftherapeutic fluid held within the barrel, the therapeutic fluidcomprising fremanezumab, and a stopper disposed within the barrel toretain the therapeutic fluid within the barrel; providing a storedspring energy for the injection spring at least 25% greater than aminimum stored spring energy required to move the stopper from the firstinitial position to the second final position without stalling, thestored spring energy being in the range from about 0.9 J to about 2 Jwhen the injection spring is in the first initial position; actuatingthe auto injector; providing an initial dispensing force to the stopperof at least about 20 N when the stopper is positioned at the firstinitial position; and providing a final dispensing force of at least 12N to the stopper when the stopper is positioned at the second finalposition, the dispensing force being at least a portion of a springforce for the injection spring. moving the stopper along the path oftravel from the first initial position to the second final positionwithin the range from about 25.7 mm to about 30 mm and within the rangefrom about 5 seconds to about 19 seconds.
 64. A method of operating anauto injector apparatus, the method comprising: providing an autoinjector holding a prefilled syringe, the auto injector comprising aninjection spring having a spring constant in the range from about 0.2N/mm to about 0.4 N/mm and a compressed length when in the first initialposition in the range from about 50 mm to about 100 mm, the injectionspring arranged to apply a dispensing force to the stopper by driving apiston rod toward the stopper, the prefilled syringe including a barrelextending along a longitudinal axis between a distal end and a proximalend, an inner diameter of the barrel being of about 8.65 mm, an innersurface of the barrel being lubricated with silicone oil in an amountbetween about 0.4 mg and about 1.1 mg before the prefilled syringe ages,the silicone oil further having a viscosity of about 1000 cSt at 25° C.before the silicon oil ages, a needle disposed at the distal end of thebarrel, the barrel defining a path of travel for the stopper, the pathof travel having a first initial position for the stopper and a secondfinal position for the stopper, the first position being an initialposition of the stopper before delivery of the therapeutic fluid, thesecond position being a final position of the stopper upon delivery of afull dose of the therapeutic fluid, the needle having an inner diameterof about 0.27 mm and a length of about 19.5 mm or less, the prefilledsyringe initially holding a volume of therapeutic fluid in the rangefrom about 1.51 mL to about 1.66 mL of therapeutic fluid held within thebarrel, the therapeutic fluid comprising fremanezumab, a viscosity ofthe therapeutic fluid being about 8.8 cSt at 22° C., a stopper disposedwithin the barrel to retain the therapeutic fluid within the barrel,providing a stored spring energy for the injection spring at least 25%greater than a minimum stored spring energy required to move the stopperfrom the first initial position to the second final position withoutstalling, the stored spring energy being in the range from about 0.9 Jto about 2 J when the injection spring is in the first initial position;actuating the auto injector; providing an initial dispensing force tothe stopper of at least about 20 N when the stopper is positioned at thefirst initial position; and providing a final dispensing force of atleast 12 N to the stopper when the stopper is positioned at the secondfinal position, the dispensing force being at least a portion of aspring force for the injection spring. moving the stopper along the pathof travel from the first initial position to the second final positionwithin the range from about 25.7 mm to about 30 mm and within the rangefrom about 5 seconds to about 19 seconds.